Compositions and methods related to POGO transposable element

Abstract

The present disclosure describes compositions and methods related to a pogo transposable element derived with KRAB domain (POGK) isoform 1, e.g., for treatment of cancers.

Description

[0001] Attorney Docket No.: BID-014PC / 110304-5014-PC

[0002] COMPOSITIONS AND METHODS RELATED TO POGO TRANSPOSABLE ELEMENT

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 63 / 688,521 , filed on August 29, 2024, the entire contents of which are incorporated herein.

[0005] FIELD

[0006] The present technology relates to compositions and methods relating to a pogo transposable element derived with KRAB domain (POGK) isoform 1.

[0007] GOVERNMENT INTEREST

[0008] This invention was made with government support under grant R01 CA249223 awarded by the National Cancer Institute (NCI). The government has certain rights in the invention.

[0009] DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0010] The instant application contains a sequence listing, which has been submitted in XML format via EFS-Web. The contents of the XML copy named “Bl D-014PC_110304-5014-PC_Sequence_Listing,” which was created on August 29, 2025 and is 270,336 bytes in size, the contents of which are incorporated herein by reference in their entirety.

[0011] BACKGROUND

[0012] Transposable elements (TEs) are indispensable for human development, with critical functions in pluripotency and embryogenesis. TE sequences are also recognized to contribute to human pathologies, especially cancer, with documented activities as cis / trans transcriptional regulators, as sources of non-coding RNAs, and as mutagens that disrupt tumor suppressors. Despite this knowledge, little is known regarding the involvement of TE-derived genes (TEGs) in tumor pathogenesis. Thus, a more complete understanding of TEGs is needed and how TEGs might be modulated to allow for effective therapies to treat cancer and other diseases.

[0013] SUMMARY

[0014] DBl / 161946556.2 1 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0015] Therefore, the present disclosure provides, in aspects, a method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 , or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.

[0016] In embodiments, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid, small molecule, or protein inhibiting pogo transposable element derived with KRAB domain (POGK) isoform 1 or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid, small molecule, or protein inhibitor of pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.

[0017] In embodiments, the nucleic acid is an expression vector. In embodiments, the expression vector is a viral vector. In embodiments, the viral vector is selected from a lentivirus vector (LV), a retrovirus vector (RV), an adenovirus vector (AV), an adeno-associated virus vector (AAV), and an a virus vector (e.g., a Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV) vector).

[0018] In embodiments, the nucleic acid is mRNA. In embodiments, the nucleic acid is a modified mRNA (mmRNA). In embodiments, the mmRNA comprises at least one modified nucleotide selected from pseudouridine (’+’), N1-methyl-pseudouridine, N6-methyladenosine (m6A), N1 -methyladenosine (m1A), 5-methylcytosine (m5C), and 5-hydroxymethylcytosine (hm5C). In embodiments, the mmRNA further comprises 5’ untranslated region (5’-UTR), and 3’ untranslated region (3’-UTR), 5' cap structure and / or 3’-poly(A) tail.

[0019] In embodiments, the nucleic acid is formulated as a lipid nanoparticle (LNP), a lipoplex, or a liposome.

[0020] In embodiments, and in a non-limiting way, the nucleic acid is selected from SEQ ID NO: 245, or a variant thereof, optionally having at least about 90%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto and / or or having about 1 to about 20 (e.g. about 1 , or about 2, or about 3, or about 4, or about 5) nucleic acid modifications, optionally selected from substitutions, additions, or deletions, or a nucleic acid that binds to a nucleic acid selected from SEQ ID NO: 245.

[0021] In embodiments, and in a non-limiting way, the nucleic acid is selected from SEQ ID NO: 246, or a variant thereof, optionally having at least about 90%, or at least about 95%, or at least about 97%, or at least about

[0022] DBl / 161946556.2 2 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0023] 98%, or at least about 99% identity thereto and / or or having about 1 to about 20 (e.g. about 1 , or about 2, or about 3, or about 4, or about 5) nucleic acid modifications, optionally selected from substitutions, additions, or deletions, or a nucleic acid that binds to a nucleic acid selected from SEQ ID NO: 246.

[0024] In embodiments, and in a non-limiting way, the nucleic acid is selected from SEQ ID NO: 247, or a variant thereof, optionally having at least about 90%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto and / or or having about 1 to about 20 (e.g. about 1 , or about 2, or about 3, or about 4, or about 5) nucleic acid modifications, optionally selected from substitutions, additions, or deletions, or a nucleic acid that binds to a nucleic acid selected from SEQ ID NO: 247.

[0025] In various aspects, disclosed herein is a method of modulating POGK transcription, translation, and / or activity comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.

[0026] In embodiments, disclosed herein is a method of modulating POGK transcription, translation, and / or activity comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid, small molecule, or protein inhibiting pogo transposable element derived with KRAB domain (POGK) isoform 1 or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid, small molecule, or protein inhibitor of pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.

[0027] In various aspects, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA and administering the cell to the subject. In embodiments, in a non-limiting approach, the isolated nucleic acid targets the KRAB domain of POGK and suppresses POGK.

[0028] In embodiments, the nucleic acid is an antisense oligonucleotide (ASO). In embodiments, the ASO inhibits the formation of mRNA encoding POGK isoform 2, and / or the ASO inhibits the formation of mRNA encoding POGK isoform 1 , and / or promotes the formation of mRNA encoding POGK isoform 1. In embodiments, the ASO promotes the inclusion of exon 2 of POGK in the mRNA, optionally wherein the ASO promotes the

[0029] DBl / 161946556.2 3 Attorney Docket No.: BID-014PC / 110304-5014-PC formation of an mRNA comprising exons 2, 3, 4, 5, and 6. In embodiments, the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long.

[0030] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of isoform 1 of POGK, optionally inhibiting splicing of isoform 1 of POGK to isoform 2 of POGK.

[0031] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK, optionally splicing of POGK to isoform 2.

[0032] In embodiments, the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long. In embodiments, the ASO is about 15 to about 20 nucleotides in length. In embodiments, the ASO is about 15 nucleotides in length. In embodiments, the ASO is about 16 nucleotides in length. In embodiments, the ASO is about 17 nucleotides in length. In embodiments, the ASO is about 18 nucleotides in length. In embodiments, the ASO is about 19 nucleotides in length. In embodiments, the ASO is about 20 nucleotides in length.

[0033] In embodiments, the ASO comprises at least one internal phosphorothioate deoxyribonucleotide. In embodiments, the ASO comprises at least two internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least three internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least four internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least five internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least six internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least seven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eight internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least nine internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least ten internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eleven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least twelve internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 8-10 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 8 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 9 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 10 internal phosphorothioate deoxyribonucleotides.

[0034] DBl / 161946556.2 4 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0035] In embodiments, the ASO comprises at least one terminal 2’-O-methylation modification. In embodiments, the ASO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the ASO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the ASO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the plurality of 2'-O-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 17 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 18 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 19 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 6-20 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9-15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11-13 residues.

[0036] In embodiments, the ASO comprises at least one terminal 2’-O-methylation or LNA modification and at least about 6, or at least about 8, or at least about 9, or at least about 10 internal deoxyribo nucleotides and / or phosphorothioate modifications. In embodiments, the ASO comprises terminal alternating 2’-O-methylation and LNA modification, combined with at least about 6, or at least about 8, or at least about 9, or at least about 10 internal deoxyribo nucleotides and / or phosphorothioate modifications.

[0037] In embodiments, the ASO comprises two 2'-O-methylation modifications. In embodiments, the ASO comprises three 2'-O-methylation modifications. In embodiments, the ASO comprises four 2'-O-methylation modifications. In embodiments, the ASO comprises five 2'-O-methylation modifications. In embodiments, the ASO comprises six 2'-O-methylation modifications. In embodiments, the ASO comprises seven 2'-O- methylation modifications. In embodiments, the ASO comprises eight 2'-O-methylation modifications. In

[0038] DBl / 161946556.2 5 Attorney Docket No.: BID-014PC / 110304-5014-PC embodiments, the ASO comprises nine 2'-O-methylation modifications. In embodiments, the ASO comprises ten 2'-O-methylation modifications. In embodiments, the ASO comprises eleven 2'-O-methylation modifications. In embodiments, the ASO comprises twelve 2'-O-methylation modifications.

[0039] In embodiments, the ASO comprises the sequence of SEQ ID NOs: 45-144, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0040] In embodiments, the ASO has perfect sequence complementarity to an RNA molecule encoding POGK. In embodiments, the ASO has partial sequence complementarity to an RNA molecule encoding POGK.

[0041] In embodiments, the nucleic acid is a splice suppressing oligonucleotide (SSO). In embodiments, the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3 and / or POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof. In embodiments, the SSO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK to isoform 2.

[0042] In embodiments, the SSO is about 15 to about 16 nucleotides in length. In embodiments, the SSO is about 15 nucleotides in length. In embodiments, the SSO is about 16 nucleotides in length.

[0043] In embodiments, the SSO comprises at least one terminal 2 -O-methylation modification. In embodiments, the SSO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the SSO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. In embodiments, the SSO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. In embodiments, the plurality of 2'-0-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues. In embodiments, the plurality of 2'-O-

[0044] DBl / 161946556.2 6 Attorney Docket No.: BID-014PC / 110304-5014-PC methylation modifications is at least 6-16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8-15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 11-13 residues. In embodiments, the SSO comprises two 2'-O-methylation modifications.

[0045] In embodiments, the SSO comprises three 2'-O-methylation modifications. In embodiments, the SSO comprises four 2'-O-methylation modifications. In embodiments, the SSO comprises five 2'-O-methylation modifications. In embodiments, the SSO comprises six 2 -O-methylation modifications. In embodiments, the SSO comprises seven 2'-O-methylation modifications. In embodiments, the SSO comprises eight 2'-O- methylation modifications. In embodiments, the SSO comprises nine 2'-0-methylation modifications. In embodiments, the SSO comprises ten 2'-O-methylation modifications. In embodiments, the SSO comprises eleven 2'-O-methylation modifications. In embodiments, the SSO comprises twelve 2'-O-methylation modifications. In embodiments, the SSO comprises thirteen 2'-O-methylation modifications. In embodiments, the SSO comprises fourteen 2'-O-methylation modifications. In embodiments, the SSO comprises fifteen 2 -O-methylation modifications. In embodiments, the SSO comprises sixteen 2'-O- methylation modifications.

[0046] In embodiments, the SSO comprises at least one locked nucleic acid (LNA). In embodiments, the SSO comprises two LNAs. In embodiments, the SSO comprises three LNAs. In embodiments, the SSO comprises four LNAs. In embodiments, the SSO comprises five LNAs. In embodiments, the SSO comprises six LNAs. In embodiments, the SSO comprises seven LNAs. In embodiments, the SSO comprises eight LNAs. In embodiments, the SSO comprises nine LNAs. In embodiments, the SSO comprises ten LNAs. In embodiments, the SSO comprises alternating 2'-O-methylation modifications and LNAs.

[0047] In embodiments, the SSO comprises at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or about 100% 2 -O-methylation modifications. In embodiments, the SSO comprises 100% 2’-O-methylation modifications. In embodiments, the SSO comprises substantially alternating 2’-O-methylation and LNA modifications. In embodiments, the SSO comprises terminal o’methylation modification, combined with substantially alternating about 3 or about 4 or about 5 or about 6 repetitions of alternating 2’-O-methylation and LNA modifications.

[0048] DBl / 161946556.2 7 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0049] In embodiments, the SSO comprises the sequence of SEO ID NOs: 145-244, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0050] In embodiments, the SSO has perfect sequence complementarity to an RNA molecule encoding POGK. In embodiments, the SSO has partial sequence complementarity to an RNA molecule encoding POGK.

[0051] In various aspects, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 1 , wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 2, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 1 , wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 2 and administering the cell to the subject. In embodiments, the nucleic acid is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA (ASO), and a guide RNA (gRNA). In embodiments, the nucleic acid has a sequence that is complementary to and / or identical to at least 10, or at least 12, or at least 14, or at least 16 contiguous nucleotides of an mRNA encoding POGK isoform 2. In embodiments, the nucleic acid has a sequence that is complementary to and / or identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1. In embodiments, the nucleic acid has a sequence that is perfectly complementary to and / or perfectly identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 . In embodiments, the nucleic acid has a sequence that is partially complementary to and / or partially identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 .

[0052] In embodiments, the nucleic acid comprises a sugar modification, backbone modification, and / or a base modification. In embodiments, the backbone modification is a phosphorothioate modification. In embodiments, the sugar modification comprises a 2'-O-methy I (2’OMe) and / or 2’-deoxy 2’-fl uoro modification. In embodiments, the base modification comprises pseudouridine, 5’-methylcytidine, N6-methyladenosine, inosine, and / or N7-methylguanosine.

[0053] In various aspects, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an inhibitor of pogo

[0054] DBl / 161946556.2 8 Attorney Docket No.: BID-014PC / 110304-5014-PC transposable element derived with KRAB domain (POGK) and / or TRIM28 or (ii) contacting a cell with a pharmaceutical composition comprising an inhibitorof pogo transposable element derived with KRAB domain (POGK) and / or TRIM28 and administering the cell to the subject. In embodiments, the inhibitor is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like inhibitor, an antibody, an antibody-like molecule, a peptide, and a peptidomimetic. In embodiments, the inhibitor reduces the amount or activity of POGK and / or TRIM28. In embodiments, the inhibitor reduces the amount or activity of at least one ribosomal protein gene. In embodiments, the ribosomal protein is selected from RPLP1 , RPL11 , RPL13, RPL15, RPL36, RPS16, RPS28, and RPS29. In embodiments, the inhibitor inhibits the transcription of one or more of RPL13, RPL15, RPS16, RPS28, and RPS29.

[0055] In embodiments, the cancer is a solid cancer, or liquid tumor, or a blood cancer. In embodiments, the cancer is an early-stage cancer. In embodiments, the cancer is a late-stage cancer. In embodiments, the cancer is a pre-metastatic cancer or a metastatic cancer. In embodiments, the cancer is a resectable tumor. In embodiments, the cancer is a carcinoma. In embodiments, the cancer is selected from a breast cancer, bone cancer, abdominal cancer, adrenal cancer, bladder cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, intestinal cancer, kidney cancer, leukemia, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma cancer, skin cancer, spleen cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulval cancer.

[0056] In embodiments, the cancer is selected from acute myeloid leukemia, adrenocortical carcinoma, bladder urothelial carcinoma, breast ductal carcinoma, breast lobular carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, esophageal carcinoma, gastric adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, lower grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, paraganglioma & pheochromocytoma, prostate adenocarcinoma, sarcoma, skin cutaneous melanoma, testicular germ cell cancer, thymoma, thyroid papillary carcinoma, uterine carcinosarcoma, uterine corpus endometrioid carcinoma, and uveal melanoma.

[0057] DBl / 161946556.2 9 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0058] In embodiments, the cancer is selected from breast cancer, pancreatic adenocarcinoma, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., lung adenocarcinoma and lung squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), ovarian cancer (e.g., ovarian serous cystadenocarcinoma).

[0059] In embodiments, the cancer is triple-negative breast cancer (TNBC).

[0060] In embodiments, the method further comprises the step of administering to the subject a second pharmaceutical composition comprising an anti-immune checkpoint agent. In embodiments, the second pharmaceutical composition is administered before administering the pharmaceutical composition. In embodiments, the pharmaceutical composition is administered before administering the second pharmaceutical composition. In embodiments, the pharmaceutical composition and the second pharmaceutical composition are contemporaneously administered.

[0061] In embodiments, the anti-immune checkpoint agent is or comprises an antibody that is capable of binding an immune checkpoint molecule. In embodiments, the antibody is capable of binding programmed cell death protein 1 (PD 1), a PD 1 ligand, and / or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). In embodiments, the antibody is capable of binding PD-1 and is optionally selected from pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), cemiplimab (LIBTAYO), pidilizumab (CT 011), dostarlimab (JEMPERLI), Spartalizumab (PDR001), RMP1-14, balstilimab (AGEN2034), Vopratelimab (JTX-4014), Camrelizumab (SHR1210), Sintilimab (IBI308), Tislelizumab (BGB-A317), Toripalimab (JS 001), INCMGA00012 (MGA012), AMP-224, and AMP-514.

[0062] In embodiments, the antibody is capable of binding PD-L1 and is optionally selected from atezolizumab (TECENTRIQ), avelumab (BAVENCIO), durvalumab (IMFINZI), KN035, a lymphocyte activation gene-3 (LAG-3, CD223) inhibitor, relatlimab (BMS-986,016), relatlimab (BMS-986,016) in combination with opdualag (nivolumab) (nivolumab and relatlimab-rmbw), and Cosibelimab (CK-301). In embodiments, the antibody is capable of binding CTLA-4 and is optionally Ipilimumab (YERVOY) or Tremelimumab (IM JUDO).

[0063] In various embodiments, the methods described herein are useful in the evaluation of a solid tumor or liquid tumor sample from a subject, or a blood cancer sample from a subject, for example, for evaluating diagnosis, prognosis, and / or response to treatment. In various aspects, the present disclosure comprises evaluating a solid tumor, liquid tumor, or a blood cancer sample from a subject. In various embodiments, the evaluation is selected from diagnosis, prognosis, and response to treatment. In some embodiments, the methods described herein are useful in predicting the aggressiveness of a solid tumor or liquid tumor sample from a subject, or a blood cancer sample from a subject.

[0064] DBl / 161946556.2 10 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0065] In some embodiments, a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment. In some embodiments, the subject is a human. In various other embodiments, the subject previously diagnosed with or identified as suffering from or having a condition may or may not have undergone treatment for a condition. In other embodiments, a subject can also be one who has not been previously diagnosed as having a condition (i.e., a subject who exhibits one or more risk factors for a condition). A “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.

[0066] In embodiments, the method further comprises selecting a subject for the treatment. In embodiments, the subject is selected for the treatment based on a reduced expression or activity of POGK in a tumor sample compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample. In embodiments, the expression or activity of POGK is assayed by evaluating the presence, absence, or level of expression or activity of POGK protein or an mRNA encoding POGK.

[0067] In various aspects, disclosed herein is a method of determining a cancer treatment for a patient, the method comprising: (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and (b) determining a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0068] In various aspects, disclosed herein is a method for selecting a subject for a cancer treatment, the method comprising: (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and (b) selecting the subject for a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0069] DBl / 161946556.2 11 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0070] In various aspects, disclosed herein is a method of treating cancer, the method comprising: (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and (b) administering to the subject for a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0071] In embodiments, the biological sample is obtained from blood, serum, saliva, plasma, a tissue sample, a fresh tissue sample, frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen.

[0072] In embodiments, the biological sample is a biopsy sample selected from endoscopic biopsy, bone marrow biopsy, endoscopic biopsy (e.g., cystoscopy, bronchoscopy and colonoscopy), needle biopsy (e.g., fine- needle aspiration, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computerized tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy and ultrasound- assisted biopsy), skin biopsy (e.g., shave biopsy, punch biopsy, and incisional biopsy) and surgical biopsy.

[0073] In embodiments, the biological sample comprises a body fluid selected from blood, plasma, serum, lacrimal fluid, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy sample, cell-containing body fluid, free floating nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swab, vaginal swab, oral swab, nasal swab, washing or lavage such as a ductal lavage or broncheoalveolar lavage, aspirate, scraping, bone marrow specimen, tissue biopsy specimen, surgical specimen, feces, other body fluids, secretions, and / or excretions, and / or cells therefrom.

[0074] In embodiments, the evaluating is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, western blotting, in cell western, immunofluorescent staining, ELISA, and fluorescent activating cell sorting (FACS) or a combination thereof.

[0075] In embodiments, the evaluating is performed by contacting the sample with an agent that specifically binds to POGK protein and / or TRIM28 protein.

[0076] DBl / 161946556.2 12 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0077] In embodiments, the agent that specifically binds to POGK protein and / or TRIM28 protein is an antibody or fragment thereof, optionally wherein the antibody is a recombinant antibody, a monoclonal antibody, a polyclonal antibody, or fragment thereof.

[0078] In embodiments, the evaluating is performed by contacting the sample with an agent that specifically binds to a nucleic acid encoding POGK protein and / or TRIM28 protein. In embodiments, the nucleic acid is mRNA or cDNA. In embodiments, the agent that specifically binds to one or more of the nucleic acids is a nucleic acid primer or probe.

[0079] In embodiments, the POGK therapy is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like inhibitor, an antibody, an antibody-like molecule, a peptide, a peptidomimetic, and a nucleic encoding POGK isoform 1. In embodiments, the POGK therapy is or comprises a nucleic acid encoding POGK isoform 1. In embodiments, the nucleic acid is DNA. In embodiments, the nucleic acid is an expression vector.

[0080] In embodiments, the expression vector is a viral vector. In embodiments, the viral vector is selected from a lentivirus vector (LV), a retrovirus vector (RV), an adenovirus vector (AV), an adeno-associated virus vector (AAV), and an a virus vector e.g., a Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV) vector).

[0081] In embodiments, the nucleic acid is mRNA. In embodiments, the nucleic acid is a modified mRNA (mmRNA). In embodiments, the mmRNA comprises at least one modified nucleotide selected from pseudouridine ( ), N1-methyl-pseudouridine, N6-methyladenosine (m6A), N1 -methyladenosine (m1A), 5-methylcytosine (m5C), and 5-hydroxymethylcytosine (hm5C). In embodiments, the mmRNA further comprises 5’ untranslated region (5’-UTR), and 3’ untranslated region (3’-UTR), 5' cap structure and / or 3’-poly(A) tail.

[0082] In embodiments, the POGK therapy is or comprises an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA. In embodiments, in a non-limiting approach, the isolated nucleic acid targets the KRAB domain of POGK and suppresses POGK.

[0083] In embodiments, the nucleic acid is an antisense oligonucleotide (ASO). In embodiments, the ASO inhibits the formation of mRNA encoding POGK isoform 2, and / or the ASO inhibits the formation of mRNA encoding POGK isoform 1 , and / or promotes the formation of mRNA encoding POGK isoform 1. In embodiments, the ASO promotes the inclusion of exon 2 of POGK in the mRNA, optionally wherein the ASO promotes the

[0084] DBl / 161946556.2 13 Attorney Docket No.: BID-014PC / 110304-5014-PC formation of an mRNA comprising exons 2, 3, 4, 5, and 6. In embodiments, the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long.

[0085] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of isoform 1 of POGK, optionally inhibiting splicing of isoform 1 of POGK to isoform 2 of POGK.

[0086] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK, optionally splicing of POGK to isoform 2.

[0087] In embodiments, the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long. In embodiments, the ASO is about 15 to about 20 nucleotides in length. In embodiments, the ASO is about 15 nucleotides in length. In embodiments, the ASO is about 16 nucleotides in length. In embodiments, the ASO is about 17 nucleotides in length. In embodiments, the ASO is about 18 nucleotides in length. In embodiments, the ASO is about 19 nucleotides in length. In embodiments, the ASO is about 20 nucleotides in length.

[0088] In embodiments, the ASO comprises at least one internal phosphorothioate deoxyribonucleotide. In embodiments, the ASO comprises at least two internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least three internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least four internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least five internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least six internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least seven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eight internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least nine internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least ten internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eleven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least twelve internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 8-10 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 8 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 9 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 10 internal phosphorothioate deoxyribonucleotides.

[0089] DBl / 161946556.2 14 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0090] In embodiments, the ASO comprises at least one terminal 2’-O-methylation modification. In embodiments, the ASO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the ASO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the ASO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the plurality of 2'-O-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 17 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 18 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 19 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 6-20 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9-15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11-13 residues.

[0091] In embodiments, the ASO comprises two 2'-O-methylation modifications. In embodiments, the ASO comprises three 2'-O-methylation modifications. In embodiments, the ASO comprises four 2'-O-methylation modifications. In embodiments, the ASO comprises five 2'-O-methylation modifications. In embodiments, the ASO comprises six 2'-O-methylation modifications. In embodiments, the ASO comprises seven 2'-O- methylation modifications. In embodiments, the ASO comprises eight 2'-O-methylation modifications. In embodiments, the ASO comprises nine 2'-O-methylation modifications. In embodiments, the ASO comprises ten 2'-O-methylation modifications. In embodiments, the ASO comprises eleven 2'-O-methylation modifications. In embodiments, the ASO comprises twelve 2'-O-methylation modifications.

[0092] DBl / 161946556.2 15 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0093] In embodiments, the ASO comprises the sequence of SEQ ID NOs: 45-144, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0094] In embodiments, the ASO has perfect sequence complementarity to an RNA molecule encoding POGK. In embodiments, the ASO has partial sequence complementarity to an RNA molecule encoding POGK.

[0095] In embodiments, the nucleic acid is a splice suppressing oligonucleotide (SSO). In embodiments, the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3 and / or POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof. In embodiments, the SSO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK to isoform 2.

[0096] In embodiments, the SSO is about 15 to about 16 nucleotides in length. In embodiments, the SSO is about 15 nucleotides in length. In embodiments, the SSO is about 16 nucleotides in length.

[0097] In embodiments, the SSO comprises at least one terminal 2 -O-methylation modification. In embodiments, the SSO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the SSO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. In embodiments, the SSO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. In embodiments, the plurality of 2'-0-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 6-16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8-15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 11-13 residues. In embodiments, the SSO comprises two 2'-O-methylation modifications.

[0098] DBl / 161946556.2 16 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0099] In embodiments, the SSO comprises three 2'-O-methylation modifications. In embodiments, the SSO comprises four 2'-O-methylation modifications. In embodiments, the SSO comprises five 2'-O-methylation modifications. In embodiments, the SSO comprises six 2 -O-methylation modifications. In embodiments, the SSO comprises seven 2'-O-methylation modifications. In embodiments, the SSO comprises eight 2'-O- methylation modifications. In embodiments, the SSO comprises nine 2'-O-methylation modifications. In embodiments, the SSO comprises ten 2'-0-methylation modifications. In embodiments, the SSO comprises eleven 2'-O-methylation modifications. In embodiments, the SSO comprises twelve 2'-O-methylation modifications. In embodiments, the SSO comprises thirteen 2'-O-methylation modifications. In embodiments, the SSO comprises fourteen 2'-0-methylation modifications. In embodiments, the SSO comprises fifteen 2 -O-methylation modifications. In embodiments, the SSO comprises sixteen 2'-O- methylation modifications.

[0100] In embodiments, the SSO comprises at least one locked nucleic acid (LNA). In embodiments, the SSO comprises two LNAs. In embodiments, the SSO comprises three LNAs. In embodiments, the SSO comprises four LNAs. In embodiments, the SSO comprises five LNAs. In embodiments, the SSO comprises six LNAs. In embodiments, the SSO comprises seven LNAs. In embodiments, the SSO comprises eight LNAs. In embodiments, the SSO comprises nine LNAs. In embodiments, the SSO comprises ten LNAs. In embodiments, the SSO comprises alternating 2'-O-methylation modifications and LNAs.

[0101] In embodiments, the SSO comprises the sequence of SEQ ID NOs: 145-244, or a variant thereof. In embodiments, the variant comprises about 1 , or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0102] In embodiments, the SSO has perfect sequence complementarity to an RNA molecule encoding POGK. In embodiments, the SSO has partial sequence complementarity to an RNA molecule encoding POGK.

[0103] In embodiments, the POGK therapy is or comprises an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 2, wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 1 , or optionally wherein the nucleic acid promotes the degradation of mRNA encoding POGK isoform 1 . In embodiments, the nucleic acid is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA (ASO), and a guide RNA (gRNA). In embodiments, the nucleic acid has a sequence that is complementary to and / or identical to at least 10, or at least 12, or at least 14, or at least 16 contiguous nucleotides of an mRNA encoding POGK isoform 2.

[0104] DBl / 161946556.2 17 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0105] In embodiments, the nucleic acid has a sequence that is complementary to and / or identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 . In embodiments, the nucleic acid has a sequence that is perfectly complementary to and / or perfectly identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 . In embodiments, the nucleic acid has a sequence that is partially complementary to and / or partially identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 .

[0106] In embodiments, the nucleic acid comprises a sugar modification, backbone modification, and / or a base modification. In embodiments, the backbone modification is a phosphorothioate modification. In embodiments, the sugar modification comprises a 2'-O-methy I (2’OMe) and / or 2’-deoxy 2’-fl uoro modification. In embodiments, the base modification comprises pseudouridine, 5’-methylcytidine, N6-methyladenosine, inosine, and / or N7-methylguanosine.

[0107] In embodiments, the POGK therapy is or comprises an inhibitor of pogo transposable element derived with KRAB domain (POGK) and / or TRIM28. In embodiments, the inhibitor is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like inhibitor, an antibody, an antibody-like molecule, a peptide, and a peptidomimetic. In embodiments, the inhibitor reduces the amount or activity of POGK and / or TRIM28.

[0108] In embodiments, the inhibitor reduces the amount or activity of at least one ribosomal protein gene. In embodiments, the ribosomal protein is selected from RPLP1 , RPL11 , RPL13, RPL15, RPL36, RPS16, RPS28, and RPS29. In embodiments, the inhibitor inhibits the transcription ofone or more of RPL13, RPL15, RPS16, RPS28, and RPS29.

[0109] In embodiments, the cancer is metastatic. In embodiments, the tumor has metastasized to a tissue or an organ.

[0110] In embodiments, the subject is a mammal. In embodiments, the mammal is a human.

[0111] In aspects, disclosed herein is a kit comprising the pharmaceutical composition of any one of the embodiments disclosed herein with instructions for use in modulating and / or modifying and / or delivering the isolated nucleic acid.

[0112] DBl / 161946556.2 18 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0113] In aspects, disclosed herein is a composition comprising an antisense oligonucleotide, wherein the composition attenuates, weakens, reduces, decreases, or ablates the splicing that results in isoform 2 of POGK, wherein: the antisense oligonucleotide comprises at least one 2'-O-methylation modifications and at least six internal phosphorothioate deoxyribonucleotides; and the antisense oligonucleotide is about 15 to about 20 nucleotides in length.

[0114] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of isoform 1 of POGK, optionally inhibiting splicing of isoform 1 of POGK, to isoform 2 of POGK.

[0115] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK, optionally splicing of POGK, to isoform 2.

[0116] In embodiments, the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long. In embodiments, the ASO is about 15 to about 20 nucleotides in length. In embodiments, the ASO is about 15 nucleotides in length. In embodiments, the ASO is about 16 nucleotides in length. In embodiments, the ASO is about 17 nucleotides in length. In embodiments, the ASO is about 18 nucleotides in length. In embodiments, the ASO is about 19 nucleotides in length. In embodiments, the ASO is about 20 nucleotides in length.

[0117] In embodiments, the ASO comprises at least one internal phosphorothioate deoxyribonucleotide. In embodiments, the ASO comprises at least two internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least three internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least four internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least five internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least six internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least seven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eight internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least nine internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least ten internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eleven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least twelve internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In

[0118] DBl / 161946556.2 19 Attorney Docket No.: BID-014PC / 110304-5014-PC embodiments, the ASO comprises at least 8-10 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 8 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 9 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 10 internal phosphorothioate deoxyribonucleotides.

[0119] In embodiments, the ASO comprises at least one terminal 2 -O-methylation modification. In embodiments, the ASO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the ASO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the ASO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the plurality of 2'-O-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 17 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 18 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 19 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 6-20 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9-15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11-13 residues.

[0120] In embodiments, the ASO comprises two 2'-O-methylation modifications. In embodiments, the ASO comprises three 2'-O-methylation modifications. In embodiments, the ASO comprises four 2'-O-methylation modifications. In embodiments, the ASO comprises five 2'-O-methylation modifications. In embodiments, the ASO comprises six 2'-O-methylation modifications. In embodiments, the ASO comprises seven 2'-O- methylation modifications. In embodiments, the ASO comprises eight 2'-0-methylation modifications. In embodiments, the ASO comprises nine 2'-O-methylation modifications. In embodiments, the ASO comprises

[0121] DBl / 161946556.2 20 Attorney Docket No.: BID-014PC / 110304-5014-PC ten 2'-O-methylation modifications. In embodiments, the ASO comprises eleven 2'-O-methylation modifications. In embodiments, the ASO comprises twelve 2'-O-methylation modifications.

[0122] In embodiments, the ASO comprises the sequence of SEQ ID NOs: 45-144, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0123] In embodiments, the ASO has perfect sequence complementarity to an RNA molecule encoding POGK.

[0124] In embodiments, the ASO has partial sequence complementarity to an RNA molecule encoding POGK.

[0125] In aspects, disclosed herein is a composition comprising an splice suppressing oligonucleotide, wherein the composition targets or suppresses the POGK gene or an isoform thereof, wherein: the splice suppressing oligonucleotide comprises at least one 2'-O-methylation modifications; and the splice suppressing oligonucleotide is about 15 to about 16 nucleotides in length.

[0126] In embodiments, the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3 and / or POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof.

[0127] In embodiments, the SSO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK to isoform 2.

[0128] In embodiments, the SSO is about 15 to about 16 nucleotides in length. In embodiments, the SSO is about 15 nucleotides in length. In embodiments, the SSO is about 16 nucleotides in length.

[0129] In embodiments, the SSO comprises at least one terminal 2 -O-methylation modification. In embodiments, the SSO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the SSO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. In embodiments, the SSO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.

[0130] In embodiments, the plurality of 2'-O-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-

[0131] DBl / 161946556.2 21 Attorney Docket No.: BID-014PC / 110304-5014-PC methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues.

[0132] In embodiments, the plurality of 2'-O-methylation modifications is at least 6-16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8-15 residues. In embodiments, the plurality of 2'- O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11-13 residues.

[0133] In embodiments, the SSO comprises two 2'-O-methylation modifications. In embodiments, the SSO comprises three 2'-O-methylation modifications. In embodiments, the SSO comprises four 2'-O-methylation modifications. In embodiments, the SSO comprises five 2'-O-methylation modifications. In embodiments, the SSO comprises six 2'-0-methylation modifications. In embodiments, the SSO comprises seven 2'-O- methylation modifications. In embodiments, the SSO comprises eight 2'-O-methylation modifications. In embodiments, the SSO comprises nine 2'-O-methylation modifications. In embodiments, the SSO comprises ten 2'-O-methylation modifications. In embodiments, the SSO comprises eleven 2'-O-methylation modifications. In embodiments, the SSO comprises twelve 2'-O-methylation modifications. In embodiments, the SSO comprises thirteen 2'-O-methylation modifications. In embodiments, the SSO comprises fourteen 2'-O-methylation modifications. In embodiments, the SSO comprises fifteen 2'-O-methylation modifications. In embodiments, the SSO comprises sixteen 2'-O-methylation modifications.

[0134] In embodiments, the SSO comprises at least one locked nucleic acid (LNA). In embodiments, the SSO comprises two LNAs. In embodiments, the SSO comprises three LNAs. In embodiments, the SSO comprises four LNAs. In embodiments, the SSO comprises five LNAs. In embodiments, the SSO comprises six LNAs. In embodiments, the SSO comprises seven LNAs. In embodiments, the SSO comprises eight LNAs. In embodiments, the SSO comprises nine LNAs. In embodiments, the SSO comprises ten LNAs. In embodiments, the SSO comprises alternating 2'-O-methylation modifications and LNAs.

[0135] DBl / 161946556.2 22 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0136] In embodiments, the SSO comprises the sequence of SEQ ID NOs: 145-244, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0137] In embodiments, the SSO has perfect sequence complementarity to an RNA molecule encoding POGK.

[0138] In embodiments, the SSO has partial sequence complementarity to an RNA molecule encoding POGK.

[0139] The details of one or more examples of the disclosure are set forth in the description below. Other features or advantages of the present disclosure will be apparent from the following drawings, detailed description of several examples, and also from the appended claims. The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0140] DESCRIPTION OF THE DRAWINGS

[0141] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

[0142] FIG. 1A, FIG. 1 B, FIG. 1 C, FIG. 1D, FIG. 1 E, FIG. 1 F, and FIG. 1G are graphs and images showing pogo transposable element derived with KRAB domain (POGK) is aberrantly expressed in triple-negative breast cancer (TNBC). FIG. 1 A is an image showing mRNA alteration (high) of transposable element-derived genes (TEGs) in breast cancer cohorts in The Cancer Genome Atlas (TCGA) data (cohort 1 , n=1 , 100; cohort 2, n=1082; cohort 3, n=817; cohort 4, n=526). FIG. 1 B is a graph and image showing POGK expression in different tissues. The left panel of FIG. 1 B is a representative immunohistochemistry of POGK staining (1 :100) in POGK-over-expressing MCF10A cells, Normal (BRN801c slide / tissue E6), Non-TNBC (BC081116e slide / tissue A2), and TNBC (BC081116e slide / tissue B7) from 290 clinical samples. The right panel of FIG. 1 B is a graph of ratios of POGK-positive and POGK-negative staining for normal and breast cancer samples in the total 290 clinical samples. P values are performed by Chi square test. FIG. 1C is a

[0143] DBl / 161946556.2 23 Attorney Docket No.: BID-014PC / 110304-5014-PC graph showing ratios of positive and negative POGK-staining for non-TNBC and TNBC samples in 223 breast cancer clinical samples. P values are performed by Chi square test. FIG. 1 D is a graph showing qRTPCR measurements of POGK mRNA expression in normal breast (n =4) and metaplastic breast cancer specimens (n=10). QRTPCR values were normalized to 18S. Data are shown as means ± sem, ***p <0.001. FIG. 1 E is a graph showing POGK mRNA levels in luminal (n=27) and basal (n=24) breast cancer cell lines from Hoeflich dataset. Violin plots represent the median (centerline) and quartiles range. The whiskers extend up to 1.5 times the IQR from the box to the smallest and largest points. **p <0.01 . FIG. 1 F is a graph showing POGK mRNA levels in luminal (n=24) and basal (n=21 ) breast cancer cell lines from CCLE. Violin plots represent the median (centerline) and quartiles range. *p <0.05. FIG. 1G is a graph showing qRTPCR measurements of POGK in indicated breast cancer cell lines (n>3). Data are shown as means ± sem, *p <0.05.

[0144] FIG. 2A, FIG. 2B, FIG. 2C, FIG. 2D, FIG. 2E, FIG. 2F, FIG. 2G, FIG. 2H, and FIG. 2I are graphs and images showing POGK inhibits TNBC growth in vitro and in vivo. FIG. 2A is a graph showing normalized colony numbers from POGK-over-expressing cells over control cells in SUM159 cells (n=6). Data are shown as means ± sem, ****p <0.0001. FIG. 2B is a graph showing normalized colony numbers from POGK-over- expressing cells over control cells in MDA-MB-231 cells (n=3). Data are shown as means ± sem, ****p <0.0001. The graph on the left panel of FIG. 2C shows the growth (volume) of orthotopic SUM159-CTRL (n=14) and SUM159-POGK (n=12) tumors in NCG mice. The graph on the right panel of FIG. 2C shows mean tumor weight (Left) at 42 days. Data are shown as means ± sem, *p <0.05, ***p <0.001 , ****p <0.0001. The graph on the left panel of FIG. 2D shows growth (volume) of orthotopic SUM159-CTRL (n=14) and SUM159-POGK (n=14) tumors in Nu / Nu mice. The graph on the right panel of FIG. 2D shows mean tumor weight (Left) at 60 days. Data are shown as means ± sem, *p <0.05. FIG. 2E is a graph showing normalized colony numbers from POGK-over-expressing cells over control 4T 1 cells (n=6). Data are shown as means ± sem, ****p <0.0001. FIG. 2F is a graph showing normalized colony numbers from POGK-over-expressing cells over control 4T07 cells (n=3). Data are shown as means ± sem, ****p <0.0001. FIG. 2G is a graph showing growth (volume) of orthotopic 4T1-CTRL (n=20) and 4T1-POGK (n=20) tumors in BALB / c mice. Data are shown as means ± sem, *p <0.05, **p <0.01 , ***p <0.001 . FIG. 2H is a graph showing mean tumor weight from 4T1-PRRL3-CTRL (n=11) and 4T1-PRRL3-POGK (n=4) groups. Data are shown as means ± sem, *p <0.05. The panel on the left of FIG. 2I shows growth (volume) of orthotopic 4T07-CTRL (n= 14) and 4T07-POGK (n=16) tumors in BALB / c mice. The panel on the right of FIG. 2I shows mean tumor weight (Left) at 14 days. Data are shown as means ± sem, *p <0.05, **p <0.01 .

[0145] DBl / 161946556.2 24 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0146] FIG. 3A, FIG. 3B, FIG. 3C, FIG. 3D, and FIG. 3E are graphs and images showing POGK causes widespread inhibition of ribosomal gene expression. FIG. 3A is a graph showing a volcano plot of differentially expressed genes (DEGs; RNA Seq data) from POGK-over-expressing SUM159 cells; the left side of FIG. 3A shows dots (dark blue dots) that are down-regulated, and the right side of FIG. 3A shows dots (brown dots) that are up-regulated DEGs, respectively. The vertical broken lines in the middle of FIG. 3A indicate fold change (FC=log2(±1)) and horizonal broken line indicates p value (p=0.05). Plot was generated from VolcaNoseR. FIG. 3B is a graph showing Pathway-Kyoto Encyclopedia of Genes and Genomes (Pathway-KEGG) analysis of POGK down DEGs from WEB-based gene set analysis toolkit. NES: normalized enrichment score; FDR: false discovery rate. FIG. 3C is an image of a GSEA enrichment plot of POGK down DEGs. NES: normalized enrichment score; FDR: false discovery rate. FIG. 3D is an image of a heatmap of gene expression ratio of ribosomal genes in POGK-over-expressing SUM159 cells versus controls. *p <0.05, **p <0.01. FIG. 3E is an image showing the estimated knockout effect score [DepMap: CRISPR gene effect 22Q2] of ribosomal proteins in SUM159, MDA-MB-231 and CAL51 cells. The negative scores represent the decrease of cancer cell viability upon the indicated CRISPR gRNA library transduction.

[0147] FIG. 4A, FIG. 4B, FIG. 4C, FIG. 4D, FIG. 4E, and FIG. 4F are graphs and images showing KRAB domain is critical for POGK function. FIG. 4A is an image showing total spectrum counts from anti-FLAG immunoprecipitation lysates. FIG. 4B is an image showing representative western blotting of TRIM28 following immunoprecipitation of FLAG-POGK overexpressed in SUM159 (left side of FIG. 4B; n=3), MDA- MB-231 (n=3; middle of FIG. 4B) and CAL51 (n=2; right side of FIG. 4B) cells. FIG. 4C is an image showing representative western blotting of POGK after immunoprecipitation of endogenous TRIM28 from SUM159 cells (n=3; left side of FIG. 4C), MDA-MB-231 (n=2; middle of FIG. 4C), and CAL51 cells (right side of FIG. 4C; n=3). The upper image in FIG. 4D is a non-limiting schematic of truncation of POGK protein major domains. The bottom image in FIG. 4D is a representative western blotting (n=2) of truncated POGK in SUM159 cells. FIG. 4E is an image showing representative western blotting (n=2) of TRIM28 in whole cell lysates (WCL), and in FLAG-immunoprecipitates of POGK with or without KRAB domain in SUM159 cells. FIG. 4F is a graph showing normalized colony counts from full length or truncated POGK-over-expressing cells over control SUM159 (n>4). Data are shown as means ± sem, **p <0.01, ****p <0.0001.

[0148] FIG. 5A, FIG. 5B, FIG. 5C, FIG. 5D, FIG. 5E, FIG. 5F, FIG. 5G, FIG. 5H, FIG. 5I, and FIG. 5J are graphs and images showing inhibition of RPS16 and RPS29 by the POGK-TRIM28 axis. FIG. 5A is an image showing a venn diagram of ribosomal protein genes that overlap between POGK-down DEGs and POGK potential binding targets by ChlP-Seq. FIG. 5B is a graph showing qRTPCR measurements (n=3) of indicated DBl / 161946556.2 25 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0149] RPL and RPS genes following transfection of TRIM28 esiRNA and esiRLUC in POGK-over-expressing and control SUM159 cells. QRTPCR values were normalized to 18S. Data are shown as means ± sem, *p <0.05, **p <0.01 , ***p <0.001. FIG. 5C is a graph showing qRTPCR measurements (n=3) of POGK, TRIM28, RPS16, and RPS29 in POGK-over-expressing CAL51 cells transfected with TRIM28 esiRNA and esiRLUC. QRTPCR values were normalized to 18S. Data are shown as means ± sem, *p <0.05, **p <0.01. FIG. 5D is a graph showing RPS16 (left side of FIG. 5D) and RPS29 (right side of FIG. 5D) protein levels in normal (n=18) and breast cancer patients (n=125) from UALCAN (CPTAC) data. **p <0.01 , ***p <0.001. Z-values represent standard deviations from the median across samples. FIG. 5E is a graph showing RPS16 (left side of FIG. 5E) and RPS29 (right side of FIG. 5E) protein levels in normal (n=18) and breast cancer subtypes (n=90) from UALCAN (CPTAC) data. Data are shown as means ± sem, *p <0.05, ***p <0.001. Z-values represent standard deviations from the median across samples. In FIG. 5F, the left panel shows a representative image of colony growth patterns of esiRLUC, esiRPSI 6 and esiRPS29 in SUM159, and the right panel of FIG. 5F shows a graph of normalized colony counts (left) using Imaged. Data are shown as means ± sem, **p <0.01, ***p <0.001. In FIG. 5G, the left panel shows representative images of colony growth patterns of esiRLUC, esiRPSI 6 and esiRPS29 in CAL51 cells, and the right panel of FIG. 5G is a graph showing normalized colony counts (left) using Imaged. Data are shown as means ± sem, **p <0.01 , ***p <0.001 . FIG. 5H is a graph showing the growth (OD value) of SUM159 and CAL51 cells at day 7 after transient transfection of esiRNA for RPS16 and RPS29, respectively. Data are shown as means ± sem, ****p <0.0001. FIG. 5I is a graph showing SUM159 growth (cell number) after transient transfection of esiRNA for RPS16 and RPS29, respectively. Data are shown as means ± sem, ***p <0.001 (at Day 4). The left panel of FIG. 5J is a graph showing representative images of anchorage-independent growth patterns of esiRLUC, esiRPSI 6 and esiRPS29 in SUM159 cells, and the right panel of FIG. 5d is a graph showing normalized colony counts (left) using Imaged. Data are shown as means ± sem, **p <0.01 .

[0150] FIG. 6A, FIG. 6B, FIG. 6C, FIG. 6D, FIG. 6E, FIG. 6F, FIG. 6G, FIG. 6H, FIG. 6I, FIG. 6 J, FIG. 6K, FIG. 6L, and FIG. 6M are graphs and images showing how isoform switching neutralizes POGK growth suppressive functions. FIG. 6A is a non-limiting schematic of POGK exons. FIG. 6B is an image showing POGK exonlevel expression (cancer vs. normal (Iog2)) in indicated cancers in TCGA. FIG. 6C is a series of graphs showing expression correlation of POGK iso 1 and iso 2 in BRCA (n=1212), PAAD (n=183), LIHC (n=423) and PRAD (n=550) from TSVdb data. FIG. 6D is a graph showing expression correlation of POGK iso 1 and iso 2 in TNBC (n=115) from TSVdb data. FIG. 6E are graphs showing qRTPCR measurements (means ± sem) of POGK mRNA expression in breast normal (n=4) and metaplastic breast cancer tissues (n=10); the

[0151] DBl / 161946556.2 26 Attorney Docket No.: BID-014PC / 110304-5014-PC left panel of FIG. 6E shows POGK iso 2 / iso 1 expression ratio; the right panel of FIG. 6E shows POGK iso 2 expression. Data are shown as means ± sem, *p <0.05, **p <0.01. FIG. 6F is a graph showing growth (volume) of orthotopic 4T1-CTRL (n=20) and 4T1-DOX-POGK iso 1 (n=20) tumors in BALB / c mice; DOX treatment started at day 12. Data are shown as means ± sem, *p <0.05. The left panel of FIG. 6G shows representative images of Ki67 immunohistochemistry in tumor tissues in (I) (n=6); The right panel of FIG. 6G quantitation of Ki67 positive cells in Left. Data are shown as means ± sem, **p <0.01. FIG. 6H is a graph showing growth (volume) of orthotopic 4T 1 -CTRL (n=16) and 4T 1 -DOX-POGK iso 2 (n=16) tumors in BALB / c mice; DOX treatment started at day 12. Data are shown as means ± sem. FIG. 6I is a graph showing qRTPCR measurements (CTRL, n=6; DOX, n=8) of POGK, mouse RPS16, mouse RPS29 expression in tumor samples from FIG. 6F. QRTPCR values were normalized to 18S. Data are shown as means ± sem, **p <0.01 , ***p <0.001. FIG. 6J are graphs showing the correlation between RPS16 (left panel of FIG. 6J) or RPS29 (right panel of FIG. 6J) with POGK iso 1 (n=115) from BRCA-TNBC clinical samples from TSVdb. FIG. 6K is a graph showing qRTPCR measurements (CTRL, n=5; DOX, n=5) of POGK, mouse RPS16, mouse RPS29 expression in tumors from FIG. 6H. QRTPCR values were normalized to 18S. Data are shown as means ± sem. FIG. 6L are graphs showing the correlation between RPS16 (left panel of FIG. 6L) or RPS29 (right panel of FIG. 6L) with POGK iso 2 (n=115) from BRCA-TNBC clinical samples in TSVdb. FIG. 6M is a non-limiting schematic diagram of POGK-mediated inhibition of RPS16 / RPS29 for cancer control.

[0152] FIG. 7A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E, and FIG. 7F are images showing mRNA alterations of TEs- derived genes in different cancers. FIG. 7A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E, and FIG. 7F show mRNA alterations of TEGs in Lung adenocarcinoma (FIG. 7A, LUAD), Lung squamous cell carcinoma (FIG. 7B, LUSC), Pancreatic adenocarcinoma (FIG. 7C, PAAD), Ovarian serous cystadenocarcinoma (FIG. 7D, OV), Liver hepatocellular carcinoma (FIG. 7E, LIHC) and Prostate adenocarcinoma (FIG. 7F, PRAD) in TOGA data.

[0153] FIG. 8A and FIG. 8B are graphs showing copy number alterations of POGK in TOGA studies. FIG. 8A is a graph showing copy number alteration frequency of POGK in 67,643 samples from 205 TOGA studies (alteration frequency greater than 5%). FIG. 8B is a graph showing copy number alteration frequency of POGK in 11 ,253 samples from 24 TOGA breast-cancer-related studies (alteration frequency greater than 2.5%).

[0154] FIG. 9A, FIG. 9B, FIG. 9C, FIG. 9D, and FIG. 9E are images and graphs showing endogenous and exogenous expression of POGK in breast cells. FIG. 9A is an image showing a representative western

[0155] DBl / 161946556.2 27 Attorney Docket No.: BID-014PC / 110304-5014-PC bloting (n=3) of POGK in breast cancer cell lines. FIG. 9B is an image showing a representative western bloting (n=3) of POGK in SUM159, MDA-MB-231 and CAL51 cells stably expressing POGK. FIG. 9C is a graph showing qRTPCR measurements of the over-expression efficiency of POGK (n=3) in SUM159 and MDA-MB-231 cells. Data are shown as means ± sem, *p <0.05, ***p <0.001. FIG. 9D is a graph showing qRTPCR measurements of the over-expression efficiency of POGK (n=3) in 4T1 and 4T07 cells. Data are shown as means ± sem, *p <0.05. FIG. 9E is an image showing a representative western blotting (n=3) of POGK in 4T1-DOX-inducible-POGK cells.

[0156] FIG. 10A, FIG. 10B, FIG. 10C, FIG. 10D, FIG. 10E, FIG. 10F and FIG. 10G are graphs and images showing POGK inhibits BCC growth in vitro and in vivo. The left panel of FIG. 10A shows representative images of colony growth patterns of controls and POGK-over-expressing-SUM159 cells (n=3). The right panel of FIG. 10A shows mean gray value of colonies in left using Imaged. Data are shown as means ± sem, **p <0.01. The left panel of FIG. 10B shows representative images of colony growth paterns of controls and POGK- over-expressing-MDA-MB-231 cells (n=3). The right panel of FIG. 10B shows normalized colony counts (left) using Imaged. Data are shown as means ± sem, ***p <0.001. The right panel of FIG. 10C shows representative images of colony growth paterns of controls and POGK-over-expressing-CAL51 cells (n=3). The right panel of FIG. 10C shows normalized colony counts (left) using Imaged. Data are shown as means ± sem, *p <0.05. FIG. 10D is a graph showing tumor incidence of SUM159 cells with or without stable overexpression of POGK in NCG mice at day 42. FIG. 10E is a graph showing tumor incidence of SUM159 cells with or without stable over-expression of POGK in Nu / Nu mice at week 8.5. FIG. 10F is a graph showing tumor incidence of 4T 1 cells with or without stable over-expression of POGK in BALB / c mice at day 22. FIG. 10G is a graph showing tumor incidence of 4T1 cells with or without stable over-expression of PRRL3-POGK in BALB / c mice at day 15.

[0157] FIG. 11A, FIG. 11 B, and FIG. 11C are graphs showing KEGG analysis of POGK-DEGs. FIG. 11A is a graph showing an ontology-GSEA enrichment plot of POGK up-DEGs, NES: normalized enrichment score; FDR: false discovery rate. FIG. 11 B is a graph showing a Gene Ontology-GSEA enrichment plot of POGK down- DEGs, NES: normalized enrichment score; FDR: false discovery rate. FIG. 11 C is a graph showing pathway- GSEA enrichment plot of POGK up-DEGs, NES: normalized enrichment score; FDR: false discovery rate.

[0158] FIG. 12A and FIG. 12B shows a graph and image of POGK localization and mass spectrometry of POGK immunoprecipitated lysates. FIG. 12A is an image of a representative picture of anti-FLAG immunofluorescence staining in SUM159-POGK-FLAG cells. Scale bar, 6.45 pm. FIG. 12B shows a

[0159] DBl / 161946556.2 28 Attorney Docket No.: BID-014PC / 110304-5014-PC representative silver staining image of polyacrylamide gel resolving POGK immunoprecipitation (anti-FLAG) from SUM159 cells. Purple arrow indicates POGK.

[0160] FIG. 13 shows an image of how POGK without KRAB domain does not affect ribosomal gene expression. FIG. 13 shows a heatmap of gene expression ratios of ribosomal proteins in POGK without KRAB domain- over-expressing SUM159 cells versus controls.

[0161] FIG. 14A, FIG. 14B, FIG. 14C, FIG. 14D, FIG. 14E, and FIG. 14F are graphs and images showing how RPS16 and RPS29 related genes are enriched in ribosomal gene sets. FIG. 14A shows GSEA analysis (C2 set) of RPS16 correlated genes (r>=0.1 and P<0.05) from METABRIC (cbioportal). FIG. 14B shows GSEA analysis (C2 set) of RPS29 correlated genes (r>=0.1 and P<0.05) from METABRIC (cbioportal). FIG. 14C shows GSEA analysis (C2 set) of RPS16 correlated genes (r>=0.1 and P<0.05) from TCGA firehose legacy (cbioportal). FIG. 14D shows RPS29 correlated genes (r>=0.1 and P<0.05) from TCGA firehose legacy (cbioportal). FIG. 14E shows correlations between RPS16 with other RPL and RPS family proteins. FIG. 14F shows RPS29 with other RPL and RPS family proteins.

[0162] FIG. 15A and FIG. 15B are graphs showing RPS16 and RPS29 regulate the expression of other ribosomal genes. FIG. 15A is a graph showing qRTPCR measurements of the over-expression efficiency of RPS16 and RPS29 following transient transfection of esiRNA-RPS16 and esiRNA-RPS29 in SUM159 cells (n=3). QRTPCR values were normalized to 18S. Data are shown as means ± sem, ****p <0.0001. FIG. 15B is a graph showing qRTPCR measurements of indicated RPLs and RPSs following transient transfection of SUM159 cells with esiRNA-RPS16 and esiRNA-RPS29 (n=3). QRTPCR values were normalized to 18S. Data are shown as means ± sem, *p <0.05, **p <0.01 , ***p <0.001.

[0163] FIG. 16A, FIG. 16B and FIG. 16C are graphs and a table showing POGK mutational status in BRCA specimens and its expression regulation by DNMT inhibitor decitabine. FIG. 16A is a table showing POGK somatic mutational status per GDC-TCGA Dataset. Total 6 POGK somatic mutations recorded in a total of 678 breast clinical samples. FIG. 16B is a graph showing alterations in POGK mutational status per COSMIC Dataset. The depicted black lines represent mutations showcasing variations at the amino acid level spanning the entire length of POGK. Notably, the uppermost line corresponds to POGK amino acid position 434, exhibiting a total of 4 mutations. FIG. 16C is a graph showing POGK expression levels after DNMT inhibitor decitabine treatment in epithelial cancer cells from GSE25428.

[0164] FIG. 17A, FIG. 17B, FIG. 17C, FIG. 17D, FIG. 17E and FIG. 17F are graphs showing the use of POGK to stratify patients with the worst outcome. FIG. 17A, FIG. 17B, FIG. 17C, FIG. 17D, FIG. 17E and FIG. 17F

[0165] DBl / 161946556.2 29 Attorney Docket No.: BID-014PC / 110304-5014-PC show POGK representing a biomarker, and indicate that POGK-low TNBC tumors give patients poorer survival than POGK-high tumors. This applies to patients whose disease went to the lymph nodes.

[0166] FIG. 18A, FIG. 18B, FIG. 18C, and FIG. 18D are images and graphs showing knockout of POGK induces cellular senescence in TNBC cells.

[0167] FIG. 19A and FIG. 19B are images and graphs showing a POGK CRISPR-pool that inhibits MDA-MB-468 cell growth.

[0168] FIG. 20A and FIG. 20B are graphs showing knockdown of POGK by shRNA inhibits cell growth in human TNBC cells.

[0169] FIG. 21 A, FIG. 21 B, FIG. 21C, FIG. 21 D, and FIG. 21 E are images and graphs showing knockdown of POGK by shRNA inhibits cell growth in mouse TNBC cells.

[0170] FIG. 22A, FIG. 22B, FIG. 22C, and FIG. 22D are images and graphs showing how POGK ASOs induce TNBCs cell death. FIG. 22A shows qRT-PCR experiments of POGK in CAL51 cells following 48-hour treatment with NC1 ASO or POGK ASOs #1-25 at 100 nM, which correspond to the following SEQ IDs: ASO1 (SEQ ID NO: 1), ASO2 (SEQ ID NO: 2), ASO3 (SEQ ID NO: 3), ASO4 (SEQ ID NO: 4), ASO5 (SEQ ID NO: 5), ASO6 (SEQ ID NO: 6), ASO7 (SEQ ID NO: 7), ASO8 (SEQ ID NO: 8), ASO9 (SEQ ID NO: 9), ASO10 (SEQ ID NO: 10), ASO11 (SEQ ID NO: 11), ASO12 (SEQ ID NO: 12), ASO13 (SEQ ID NO: 13), ASO14

[0171] (SEQ ID NO: 14), ASO15 (SEQ ID NO: 15), ASO16 (SEQ ID NO: 16), ASO17 (SEQ ID NO: 17), ASO18

[0172] (SEQ ID NO: 18), ASO19 (SEQ ID NO: 19), ASO20 (SEQ ID NO: 20), ASO21 (SEQ ID NO: 21), ASO22

[0173] (SEQ ID NO: 22), ASO23 (SEQ ID NO: 23), ASO24 (SEQ ID NO: 24) and ASO25 (SEQ ID NO: 25). FIG.

[0174] 22B shows western blot experiments in CAL51 cells following 48-hour treatment with NC1 ASO or POGK ASOs (#4, #20, #21) at 100 nM. POGK ASOs #4, #20, #21 correspond to the following SEQ IDs: ASO4 (SEQ ID NO: 4), ASO20 (SEQ ID NO: 20), and ASO21 (SEQ ID NO: 21). FIG. 22C shows apoptosis cell ratio experiments of CAL51 cells following 48-hour treatment with NC1 ASO or POGK ASOs (#4, #20, #21) at 100 nM. POGK ASOs #4, #20, #21 correspond to the following SEQ IDs: ASO4 (SEQ ID NO: 4), ASO20 (SEQ ID NO: 20), and ASO21 (SEQ ID NO: 21). FIG. 22D shows qRT-PCR experiments of POGK in MDA- MB-468 cells following 48-hour treatment with NC1 ASO or POGK ASOs (#4, #20, #21) at 100 nM. POGK ASOs #4, #20, #21 correspond to the following SEQ IDs: ASO4 (SEQ ID NO: 4), ASO20 (SEQ ID NO: 20), and ASO21 (SEQ ID NO: 21).

[0175] DBl / 161946556.2 30 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0176] FIG. 23A and FIG. 23B are graphs showing how POGK SSOs inhibit TNBCs cellular growth. FIG. 23A shows cell growth ratio experiments of CAL51 cells treated with NC or POGK SSO1 (SEQ ID NO: 145), SSO2 (SEQ ID NO: 146), SSO3 (SEQ ID NO: 147), SSO4 (SEQ ID NO: 148), SSO5 (SEQ ID NO: 149), or SSO6 (SEQ ID NO: 150) at 100 nM, measured on day 4 relative to day 1 using WST-1 assay. FIG. 23B shows cell growth ratio experiments of CAL51 cells treated with NC or POGK SSO4 (SEQ ID NO: 148), at 100 nM, measured on day 4 relative to day 1 using WST-1 assay.

[0177] DETAILED DESCRIPTION

[0178] Prior to the present disclosure, the understanding of cis and trans functions of transposable element (TE) sequences in cancer, as well as the contributions of exapted TE-derived genes (TEGs) remained incompletely understood. The present disclosure demonstrates, inter alia, unbiased analyses of TEG expression across several human cancer cohorts and identified the pogo transposable element derived with KRAB domain (or POGK) as the most recurrently deregulated mRNA across many tumors, especially breast. The present disclosure shows, inter alia, how POGK was surprisingly and particularly down-regulated in triple-negative breast cancer (TNBC) - an aggressive hormone-negative subtype that currently lacks targeted therapeutics - and it potently inhibited the growth of TNBC cells in cellular and animal models. The present disclosure and experiments described herein demonstrate, inter alia, how POGK coupled with the transcriptional co-repressor TRIM28, directly blocks the transcription of ribosomal proteins, thereby causing widespread inhibition of ribosomal biogenesis. Accordingly, present disclosure demonstrates, inter alia, that POGK undergoes post-transcriptional isoform switching that causes deactivation of its growth inhibitory activities in TNBC development. Collectively, the present disclosure introduces previously unknown, tumorsuppressive functions for TE-derived POGK in TNBC pathogenesis and highlight its role as a potential therapeutic target in clinical disease.

[0179] Therefore, the present disclosure provides, in aspects, a method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 , or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject. In embodiments, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid, small molecule, or protein inhibiting pogo transposable element derived with KRAB domain

[0180] DBl / 161946556.2 31 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0181] (POGK) isoform 1 or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid, small molecule, or protein inhibitor of pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.

[0182] In embodiments, the nucleic acid is DNA.

[0183] In embodiments, the nucleic acid is an expression vector, and the expression vector is viral vector. Many viral vectors useful for gene therapy are known (see, e.g., Lundstrom, Trends Biotechnol., 21 : 1 17, 122, 2003. Illustrative viral vectors include those selected from Antiviruses (LV), retroviruses (RV), adenoviruses (AV), adeno-associated viruses (AAV), and a viruses, though other viral vectors may also be used. For in vivo uses, viral vectors that do not integrate into the host genome are suitable for use, such as a viruses and adenoviruses. Illustrative types of a viruses include Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV). For in vitro uses, viral vectors that integrate into the host genome are suitable, such as retroviruses, AAV, and Antiviruses. In embodiments, the expression vector is a viral vector. In embodiments, the viral vector is selected from a lentivirus vector (LV), a retrovirus vector (RV), an adenovirus vector (AV), an adeno-associated virus vector (AAV), and an a virus vector (e.g., a Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV) vector).

[0184] In embodiments, the nucleic acid is DNA or RNA. In embodiments, the RNA is mRNA, which is optionally modified mRNA (mmRNA). In embodiments, the mmRNA comprises at least one modified nucleotide selected from pseudouridine (4^), N1-methyl-pseudouridine, N6-methyladenosine (m6A), N1- methyladenosine (m1A), 5-methylcytosine (m5C), and 5-hydroxymethylcytosine (hm5C). In embodiments, the mmRNA further comprises 5’ untranslated region (5’-UTR), and 3’ untranslated region (3’-UTR), 5' cap structure and / or 3’-poly(A) tail.

[0185] In embodiments, the nucleic acid is formulated as a lipid nanoparticle (LNP), a lipoplex, or a liposome.

[0186] In embodiments, and in a non-limiting way, the nucleic acid is selected from a human pogo transposable element derived with KRAB (POGK) domain. An exemplary human POGK domain sequence is provided as National Center for Biotechnology Information (NCBI) Reference Sequence: Q9P215.2 (SEQ ID NO: 245). In SEQ ID NO: 245, or a variant thereof, optionally having at least about 90%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto and / or or having about 1 to about 20 (e.g. about 1 , or about 2, or about 3, or about 4, or about 5) nucleic acid modifications, optionally selected from substitutions, additions, or deletions, or a nucleic acid that binds to a nucleic acid selected from SEQ ID NO: 245.

[0187] DBl / 161946556.2 32 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0188] In embodiments, and in a non-limiting way, the nucleic acid is selected from human pogo transposable element derived with KRAB (POGK) domain isoform 1. An exemplary human POGK domain isoform 1 sequence is provided as National Center for Biotechnology Information (NCBI) Reference Sequence: NP_060012.3 (SEQ ID NO: 246). In embodiments, and in a non-limiting way, the nucleic acid is selected from SEQ ID NO: 246, or a variant thereof, optionally having at least about 90%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto and / or or having about 1 to about 20 (e.g. about 1 , or about 2, or about 3, or about 4, or about 5) nucleic acid modifications, optionally selected from substitutions, additions, or deletions, or a nucleic acid that binds to a nucleic acid selected from SEQ ID NO: 246.

[0189] In embodiments, and in a non-limiting way, the nucleic acid is selected from human pogo transposable element derived with KRAB (POGK) domain isoform 2. An exemplary human POGK domain isoform 2 sequence is provided as National Center for Biotechnology Information (NCBI) Reference Sequence: NP_001300943.1 (SEQ ID NO: 247). In embodiments, and in a non-limiting way, the nucleic acid is selected from SEQ ID NO: 247, or a variant thereof, optionally having at least about 90%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto and / or or having about 1 to about 20 (e.g. about 1 , or about 2, or about 3, or about 4, or about 5) nucleic acid modifications, optionally selected from substitutions, additions, or deletions, or a nucleic acid that binds to a nucleic acid selected from SEQ ID NO: 247.

[0190] In various aspects, disclosed herein is a method of modulating POGK transcription, translation, and / or activity comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.

[0191] In embodiments, disclosed herein is a method of modulating POGK transcription, translation, and / or activity comprising: administering to the subject a pharmaceutical composition comprising an isolated nucleic acid, small molecule, or protein inhibiting pogo transposable element derived with KRAB domain (POGK) isoform 1 or (iv) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid, small molecule, or protein inhibitor of pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.

[0192] DBl / 161946556.2 33 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0193] In various aspects, disclosed herein is a method of treating cancer in a subject in need thereof, the method the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA and administering the cell to the subject. In embodiments, in a non-limiting approach, the isolated nucleic acid targets the KRAB domain of POGK and suppresses POGK.

[0194] In embodiments, the nucleic acid is an antisense oligonucleotide (ASO). In embodiments, the ASO inhibits the formation of mRNA encoding POGK isoform 2, and / or the ASO inhibits the formation of mRNA encoding POGK isoform 1 , and / or promotes the formation of mRNA encoding POGK isoform 1. In embodiments, the ASO promotes the inclusion of exon 2 of POGK in the mRNA, optionally wherein the ASO promotes the formation of an mRNA comprising exons 2, 3, 4, 5, and 6. In embodiments, the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long.

[0195] In embodiments, the ASO inhibits the formation of an mRNA encoding POGK isoform 1 and / or POGK isoform 2. Without wishing to be bound by theory, the nucleic acid is a short hairpin RNA (shRNA) that is capable of knocking out POGK isoform 1 , and / or POGK isoform 2. In embodiments, the ASO reduces, decreases, inhibits or knocks out POGK isoform 1. In embodiments, the ASO reduces, decreases, inhibits or knocks out POGK isoform 2. In embodiments, the ASO reduces, decreases, inhibits or knocks out POGK isoform 1 , and / or POGK isoform 2. In embodiments, the present methods provide for reduction, inhibition or knock out of POGK isoform 1.

[0196] In embodiments, the present methods provide for reduction, inhibition or knock out of POGK isoform 2. In embodiments, the present methods provide for reduction, inhibition or knock out of POGK isoform 1 and / or POGK isoform 2. In embodiments, there is provided a cell demonstrating reduced, decreased, inhibited or knocked-out POGK isoform 1 .

[0197] In embodiments, there is provided a cell demonstrating reduced, decreased, inhibited or knocked-out POGK isoform 2. In embodiments, there is provided a cell demonstrating reduced, decreased, inhibited or knocked- out POGK isoform 1 and / or POGK isoform 2.

[0198] In embodiments herein, knockout of POGK isoform 1 results in cellular senescence.

[0199] DBl / 161946556.2 34 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0200] In embodiments, without wishing to be bound by theory, disclosed herein is a cell over-expressing POGK isoform 1. In embodiments, disclosed herein is a cell over-expressing POGK isoform 1 and / or inhibiting POGK isoform 2. In embodiments, disclosed herein is a cell over-expressing POGK isoform 1, and / or a cell that has a knockout POGK isoform 2. In embodiments, the present methods provide for an increase, stimulation or over-expression of POGK isoform 1 and / or a reduction, inhibition or knock out of POGK isoform 2.

[0201] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of isoform 1 of POGK, optionally inhibiting splicing of isoform 1 of POGK to isoform 2 of POGK.

[0202] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK, optionally splicing of POGK to isoform 2.

[0203] In embodiments, the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long. In embodiments, the ASO is about 15 to about 20 nucleotides in length. In embodiments, the ASO is about 15 nucleotides in length. In embodiments, the ASO is about 16 nucleotides in length. In embodiments, the ASO is about 17 nucleotides in length. In embodiments, the ASO is about 18 nucleotides in length. In embodiments, the ASO is about 19 nucleotides in length. In embodiments, the ASO is about 20 nucleotides in length.

[0204] In embodiments, the ASO comprises at least one internal phosphorothioate deoxyribonucleotide. In embodiments, the ASO comprises at least two internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least three internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least four internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least five internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least six internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least seven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eight internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least nine internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least ten internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eleven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least twelve internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In

[0205] DBl / 161946556.2 35 Attorney Docket No.: BID-014PC / 110304-5014-PC embodiments, the ASO comprises at least 8-10 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 8 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 9 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 10 internal phosphorothioate deoxyribonucleotides.

[0206] In embodiments, the ASO comprises at least one terminal 2 -O-methylation modification. In embodiments, the ASO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the ASO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the ASO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the plurality of 2'-O-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 17 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 18 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 19 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 6-20 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9-15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11-13 residues.

[0207] In embodiments, the ASO comprises two 2'-O-methylation modifications. In embodiments, the ASO comprises three 2'-O-methylation modifications. In embodiments, the ASO comprises four 2'-O-methylation modifications. In embodiments, the ASO comprises five 2'-O-methylation modifications. In embodiments, the ASO comprises six 2'-O-methylation modifications. In embodiments, the ASO comprises seven 2'-O- methylation modifications. In embodiments, the ASO comprises eight 2'-O-methylation modifications. In embodiments, the ASO comprises nine 2'-O-methylation modifications. In embodiments, the ASO comprises

[0208] DBl / 161946556.2 36 Attorney Docket No.: BID-014PC / 110304-5014-PC ten 2'-O-methylation modifications. In embodiments, the ASO comprises eleven 2'-O-methylation modifications. In embodiments, the ASO comprises twelve 2'-O-methylation modifications.

[0209] In embodiments, the ASO comprises the sequence of SEQ ID NOs: 45-144, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0210] In embodiments, the ASO has perfect sequence complementarity to an RNA molecule encoding POGK. In embodiments, the ASO has partial sequence complementarity to an RNA molecule encoding POGK.

[0211] In embodiments, the ASO is selected from Table 6, or a variant thereof. In embodiments, the variant comprises about 1 , or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0212] In embodiments, the nucleic acid is a splice suppressing oligonucleotide (SSO). In embodiments, the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3 and / or POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof. In embodiments, the SSO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK to isoform 2.

[0213] In embodiments, the SSO is about 15 to about 16 nucleotides in length. In embodiments, the SSO is about 15 nucleotides in length. In embodiments, the SSO is about 16 nucleotides in length.

[0214] In embodiments, the SSO comprises at least one terminal 2 -O-methylation modification. In embodiments, the SSO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the SSO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. In embodiments, the SSO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. In embodiments, the plurality of 2'-0-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 14 residues. In

[0215] DBl / 161946556.2 37 Attorney Docket No.: BID-014PC / 110304-5014-PC embodiments, the plurality of 2 -O-methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 6-16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8-15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11-13 residues. In embodiments, the SSO comprises two 2'-O-methylation modifications.

[0216] In embodiments, the SSO comprises three 2'-O-methylation modifications. In embodiments, the SSO comprises four 2'-O-methylation modifications. In embodiments, the SSO comprises five 2'-O-methylation modifications. In embodiments, the SSO comprises six 2 -O-methylation modifications. In embodiments, the SSO comprises seven 2'-O-methylation modifications. In embodiments, the SSO comprises eight 2'-O- methylation modifications. In embodiments, the SSO comprises nine 2'-O-methylation modifications. In embodiments, the SSO comprises ten 2'-0-methylation modifications. In embodiments, the SSO comprises eleven 2'-O-methylation modifications. In embodiments, the SSO comprises twelve 2'-O-methylation modifications. In embodiments, the SSO comprises thirteen 2'-O-methylation modifications. In embodiments, the SSO comprises fourteen 2'-O-methylation modifications. In embodiments, the SSO comprises fifteen 2 -O-methylation modifications. In embodiments, the SSO comprises sixteen 2'-O- methylation modifications.

[0217] In embodiments, the SSO comprises at least one locked nucleic acid (LNA). In embodiments, the SSO comprises two LNAs. In embodiments, the SSO comprises three LNAs. In embodiments, the SSO comprises four LNAs. In embodiments, the SSO comprises five LNAs. In embodiments, the SSO comprises six LNAs. In embodiments, the SSO comprises seven LNAs. In embodiments, the SSO comprises eight LNAs. In embodiments, the SSO comprises nine LNAs. In embodiments, the SSO comprises ten LNAs. In embodiments, the SSO comprises alternating 2'-O-methylation modifications and LNAs.

[0218] In embodiments, the SSO comprises the sequence of SEQ ID NOs: 145-244, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0219] In embodiments, the SSO has perfect sequence complementarity to an RNA molecule encoding POGK. In embodiments, the SSO has partial sequence complementarity to an RNA molecule encoding POGK.

[0220] DBl / 161946556.2 38 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0221] In embodiments, the SSO is selected from Table 7, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0222] In embodiments, the nucleic acid comprises a sugar modification, backbone modification, and / or a base modification. In embodiments, the backbone modification is a phosphorothioate modification. In embodiments, the sugar modification comprises a 2'-O-methy I (2’OMe) and / or 2’-deoxy 2’-fl uoro modification. In embodiments, the base modification comprises pseudouridine, 5’-methylcytidine, N6-methyladenosine, inosine, and / or N7-methylguanosine.

[0223] In various aspects, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an inhibitor of pogo transposable element derived with KRAB domain (POGK) and / or TRIM28 or (ii) contacting a cell with a pharmaceutical composition comprising an inhibitorof pogo transposable element derived with KRAB domain (POGK) and / or TRIM28 and administering the cell to the subject. In embodiments, the inhibitor is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like inhibitor, an antibody, an antibody-like molecule, a peptide, and a peptidomimetic. In embodiments, the inhibitor reduces the amount or activity of POGK and / or TRIM28. In embodiments, the inhibitor reduces the amount or activity of at least one ribosomal protein gene. In embodiments, the ribosomal protein is selected from RPLP1 , RPL11, RPL13, RPL15, RPL36, RPS16, RPS28, and RPS29. In embodiments, the inhibitor inhibits the transcription of one or more of RPL13, RPL15, RPS16, RPS28, and RPS29.

[0224] Transposable elements

[0225] Transposable elements (TEs) encompass ubiquitous genetic units that have had critical roles in promoting genomic diversification in prokaryotes, fungi, plants, protists, and eukaryotes throughout evolution. They are divided into two major groups: class I retrotransposons that replicate themselves in a "copy-and-paste" mechanism through an RNA intermediate, and class II DNA transposons, which transpose from a donor site to a recipient site in a "cut-and paste" or “peel-and-paste” manner. Each of these classes in turn includes multiple families of TEs. Thus, class I incorporates long terminal repeat (LTR) retrotransposons and non- LTR-containing Long interspersed elements (LINEs), Small interspersed elements (SINEs), SINE— variable number tandem repeat (VNTR)-Alu (SVAs). Similarly, class II comprises the Crypton, Helitron,

[0226] DBl / 161946556.2 39 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0227] Maverick / Polinton, and the DDE TEs. Advances in human genomics, enabled by methodological breakthroughs in deep sequencing and computational biology, have brought about deeper knowledge of the origins and diversity of TEs and have sparked renewed interests in investigating their contributions to human biology.

[0228] Initially acting as “jumping genes” that cause insertional mutagenesis, the majority of TEs have been rendered immobile and their transposition activities have been largely quiesced in the human genome, for example, by epigenetic mechanisms or by mutations in their flanking 5’ and 3’ inverted repeats. Their influences, however, have persisted, with their descendent sequences serving roles, among others, as transcription factor binding sites, as enhancers and promoters regulating gene expression, or as sequences that generate non-coding RNAs. Some TE sequences also code for proteins that have indeed played beneficial homeostatic, “exapted” or “domesticated” functions in human biology. Examples here include the Ty3 / Gypsy- derived ARC protein that is involved in neuronal communication, the ERV-derived Syncytin (or ERVW) of critical importance in placental development, or the recombination activating genes 1 / 2 (RAG1 / 2) proteins involved in V(D) J recombination. Such concerted roles have rendered TEs major regulators of critical cellular and organismal processes, such as pluripotency and embryogenesis.

[0229] TE sequences are intimately associated with cancer pathogenesis. This is illustrated by the retrotransposon LINE-1 (or L1), considered to be the last active self-replicating TE in humans. Here, de-repression of the otherwise silenced L1 in pre-neoplastic lesions leads to accumulation of its open reading frame proteins 1 and 2 (ORF1 p and ORF2p), which together chaperone the L1 RNA back to the nucleus and catalyze its transposition into recipient genomic loci. Such mutagenic disruptions consequently cause amplification of oncogenes or ablation of tumor suppressor gene sequences and have been observed in a variety of solid cancers. Interestingly, L1 -produced ORF1p is found overexpressed in a variety of carcinomas and in many cases, can be used as a circulating peripheral blood biomarker of disease. TEs can also generate non-coding RNAs of important regulatory functions in cancer, such as HERV-H, which localizes with BRD4 and modulates its activity towards gene targets in colorectal cancer. In other respects, TE genomic sequences act as onco-promoters and onco-enhancers in tumorigenesis and examples of this activity include several LTRs in acute myeloid leukemia or Hodgkin’s lymphoma. Finally, emerging research has documented the abilities of ERVs to form double stranded RNAs (dsRNAs), RNA-DNA hybrids, chimeric transcripts, or promote the formation of neo-splicing events, therefore contributing to cancer-specific neoantigen generation and tumor immunogenicity.

[0230] DBl / 161946556.2 40 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0231] The present disclosure describes the involvement of TE-derived sequences in human cancer, and the identification of a prominent role for POGK as a negative regulator of TNBC development. Disclosed herein is evidence that POGK acts mechanistically as a co-repressor with TRIM28 that particularly inhibits RPS16 and RPS29 transcription, thereby widely suppressing ribosome gene synthesis and cellular growth (FIG. 6M). Disclosed herein is the introduction of a model in which POGK isoform switching (via exon skipping) promotes the downregulation of POGK in TNBC. These are previously unreported functions for POGK in tumor development in general and in breast cancer in specific that illustrate a renewed vision of how class II transposons regulate disease pathogenesis.

[0232] DNA Transposases

[0233] DNAtransposases have been essential contributors to genetic diversity, buttheir transposition / recombination activities have subsided during evolution and they are now generally considered to be inactive. However, two prominent exceptions to this notion are proteins that kept some functions of their ancestral TEs. First are the RAG1 / 2 recombinases, which promote the DNA rearrangement of the V(D)J cassettes in lymphocytes, and whose aberrant expression in blood cancers leads to the formation of translocations and gene fusions that trigger malignancy. Second, piggyBac transposable element derived 5 (or PGBD5) causes breakpoint formation, rearrangement, and inactivation of target tumor suppressor genes by associating with PGBD5- specific signal (PSS) sequences in their target DNA. Disclosed herein is the observation that deletion of its DDE_1 domain (which contains the conserved divalent-metal-binding triad of acidic amino acids essential for the enzymatic reaction) has no effect on the protein’s ability to inhibit anchorage-independent growth (FIG. 4F), which suggests that the tumor suppressive functions described herein are independent of its potential catalytic activities. Instead, the present disclosure describes how POGK acts as a transcription factor in a manner akin to CENP-B or zinc finger BED-type containing 6 (ZBED6) DNA transposases, and RPS16 and RPS29 are identified as two downstream targets of POGK.

[0234] The present disclosure identifies TRIM28, also known as transcriptional intermediary factor 1 (or TIF1 0) and KRAB-associated protein 1 (or KAP1), as a vital partner of POGK in inhibiting RPS16 and RPS29 expression. TRIM28 is a scaffold transcriptional repressor whose established functions include the assembly of multimeric complexes that cooperate in shutting down target chromatin loci. Indeed, TRIM28 associates with KRAB domains in ZNF-related proteins through its RING-B box-coiled-coil (RBCC) domain, binds to Heterochromatin protein 1 (HP1) via its PxVxL pentapeptide motif, and recruits the Nucleosome Remodeling Deacetylase NuRD and the Histone-lysine N-methyltransferase SETDB1 using its PHD and BROMO

[0235] DBl / 161946556.2 41 Attorney Docket No.: BID-014PC / 110304-5014-PC domains. The combined actions of this complex result in the deacetylation and subsequent hypermethylation of nucleosomal H3K9me3, chromatin condensation, and gene silencing. POGK in this scheme would serve as a transcriptional guide that marks the chromatin regions that need to be silenced. It is worth noting, however, that TRIM28 can also serve in some instances as a transcriptional activator (e.g., in the case where it relieves TRIM28 inhibition of hTERT expression, or in regulating RNA Pol II pausing and transcriptional elongation. TRIM28 additionally acts as an E3 ubiquitin-ligase, promoting, for example, BCL2A1 ubiquitination in mitochondria. Considering these activities, POGK may partner with TRIM28 in other functions and in other cellular compartments under certain conditions, leaving open the possibility of POGK assuming additional yet-to-be-investigated roles in cellular homeostasis.

[0236] Ribosomal protein anomalies (e.g, mutations, aberrant expressions) have been associated with a variety of diseases called ribosomopathies. Indeed, RPS and RPL proteins play ordered roles in the assembly and maturation of the 40S and 60S ribosomal RNAs (rRNAs), respectively. Accordingly, they are critical for ribosome biogenesis and deviations in their recruitment sequences or in their stoichiometry, for example, cause deleterious effects on mRNA translation, thereby affecting cellular behavior. In cancer, hyperactive ribosome biogenesis drives tumorigenesis and is required for cancer development and progression. In this regard, a number of RPS and RPL proteins have been implicated as regulators of cancer pathogenesis, including RPS16 in hepatocellular carcinoma. Although no prior reports have connected RPS29 to tumor development directly, dysfunctional RPS29 mutations were found to be associated with Diamond-Blackfan anemia, a disease that predisposes to blood dysplasia and neoplasia. How these two RPSs exert their functions in detail and why they are essential for cell survival in TNBC remains to be determined. Of note, the roles of RPS proteins in POGK activities are described herein, and thus it is important to note that POGK also affects the expressions of RPL proteins too, suggesting that it extends its regulatory reach to 60S subunit biogenesis too, thereby controlling ribosome biogenesis at different nodes.

[0237] Further, the present disclosure shows that POGK long isoform (isoform 1 ) is down-regulated in breast cancer concomitant with an up-regulation of its short isoform (isoform 2). This is consistent with other observations that recorded domain loss and emergence of shorter POGK species while conducting large-scale computational analyses of RNA-seq data in renal clear cell carcinoma and thyroid carcinoma, altogether indicative of POGK isoform switching in neoplastic tissues. Exon skipping and isoform switches are important features in cancers, especially in disrupting the activities of tumor suppressor genes or in converting them into oncogenes. Examples include the skipping of exon 7 in Muscleblind-like 1 in prostate cancer (MBNL1), the isoform switching of Estrogen Receptor 01 to 05 in Glioblastoma, the skipping of exon 11 in p73a to p73y

[0238] DBl / 161946556.2 42 Attorney Docket No.: BID-014PC / 110304-5014-PC switch in prostate cancer, or depletion of the tumor suppressor S6K1 iso-1 in favor of pro-tumorigenic shorter S6K1 isoforms in breast cancer. Interestingly, isoform switching interventions represent tractable directions in cancer therapy, with several approaches already at the proof-of-principle stage. In this regard, and considering the potency of POGK iso1 (and not iso2) in suppressing ribosome biogenesis and cancer growth, a POGK iso2-to-iso1 switch therapy may be a worthwhile endeavor in the management of TNBC and other cancers.

[0239] Cancer

[0240] Cancer is a group of diseases characterized by uncontrolled cell division which can lead to abnormal tissue and, in turn, disruption of normal physiologic processes and, possibly, death. Cancers have various etiologies and may be responsive to agents that affect aspects of these etiologies. For example, a reduction or loss of nucleic acids that are linked to cancer development may prove fruitful in the treatment of various cancers, including blood-based cancers and breast cancers. Such treatments may replace or supplement existing treatments.

[0241] In some embodiments, the present disclosure encompasses methods of treating or preventing cancer and / or a metastasis in a subject in need thereof.

[0242] In various aspects, disclosed herein are methods of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 1 , wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 2, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 1 , wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 2 and administering the cell to the subject. In embodiments, the nucleic acid is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA (ASO), and a guide RNA (gRNA). In embodiments, the nucleic acid has a sequence that is complementary to and / or identical to at least 10, or at least 12, or at least 14, or at least 16 contiguous nucleotides of an mRNA encoding POGK isoform 2. In embodiments, the nucleic acid has a sequence that is complementary to and / or identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1. In embodiments, the nucleic acid has a sequence that is perfectly complementary to and / or perfectly identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous

[0243] DBl / 161946556.2 43 Attorney Docket No.: BID-014PC / 110304-5014-PC nucleotides of an mRNA encoding POGK isoform 1 . In embodiments, the nucleic acid has a sequence that is partially complementary to and / or partially identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 .

[0244] In embodiments, the cancer is a solid cancer, or liquid tumor, or a blood cancer. In embodiments, the cancer is an early-stage cancer. In embodiments, the cancer is a late-stage cancer. In embodiments, the cancer is a pre-metastatic cancer or a metastatic cancer. In embodiments, the cancer is a resectable tumor. In embodiments, the cancer is a carcinoma.

[0245] In some embodiments, representative cancers and / or tumors and / or metastases of the present invention include breast cancer, bone cancer, abdominal cancer, adrenal cancer, bladder cancer, blood cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, intestinal cancer, kidney cancer, leukemia, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma cancer, skin cancer, spleen cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulval cancer.

[0246] In embodiments, the cancer is selected from acute myeloid leukemia, adrenocortical carcinoma, bladder urothelial carcinoma, breast ductal carcinoma, breast lobular carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, esophageal carcinoma, gastric adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, lower grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, paraganglioma & pheochromocytoma, prostate adenocarcinoma, sarcoma, skin cutaneous melanoma, testicular germ cell cancer, thymoma, thyroid papillary carcinoma, uterine carcinosarcoma, uterine corpus endometrioid carcinoma, and uveal melanoma.

[0247] In embodiments, the cancer is selected from breast cancer, pancreatic adenocarcinoma, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., lung adenocarcinoma and lung squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), ovarian cancer (e.g., ovarian serous cystadenocarcinoma).

[0248] In embodiments, the cancer is triple-negative breast cancer (TNBC).

[0249] As used herein, the term subject or patient refers to any vertebrate including, without limitation, humans and other primates (e.g., chimpanzees and other apes and monkey species), farm animals (e.g., cattle, sheep, pigs, goats, and horses), domestic mammals (e.g., dogs and cats), laboratory animals (e.g., rodents such as

[0250] DBl / 161946556.2 44 Attorney Docket No.: BID-014PC / 110304-5014-PC mice, rats, and guinea pigs), and birds (e.g., domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0251] Pharmaceutical Compositions

[0252] Another embodiment of the present disclosure is a pharmaceutical composition, or use of pharmaceutical composition, comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 , or an inhibitor thereof. Where clinical applications are contemplated, pharmaceutical compositions may be prepared in a form appropriate for the intended application. Generally, this will entail preparing compositions that are essentially free of pyrogens, as well as other impurities that could be harmful to humans or animals.

[0253] In embodiments, the methods disclosed herein further comprise the step of administering to the subject a second pharmaceutical composition comprising an anti-immune checkpoint agent. In embodiments, the second pharmaceutical composition is administered before administering the pharmaceutical composition. In embodiments, the pharmaceutical composition is administered before administering the second pharmaceutical composition. In embodiments, the pharmaceutical composition and the second pharmaceutical composition are contemporaneously administered. An effective dose is an amount sufficient to affect a beneficial or desired clinical result.

[0254] A beneficial or desired clinical result may include, inter alia, a reduction in tumor size and / or tumor growth and / or a reduction of a cancer marker that is associated with the presence of cancer as compared to what is observed without administration of the small molecule or peptide agent. A beneficial or desired clinical result may also include, inter alia, an increased presence of a marker that is associated with a reduction of cancer as compared to what is observed without administration of the small molecule or peptide agent. Also included in a beneficial or desired clinical result is, inter alia, an increased amount of a gene comprising a marker linked to cancer etiology as compared to what is observed without administration of the inhibitor. The gene comprising a marker linked to cancer etiology may include, for example, an immune checkpoint gene, such as PD-1 , PD-L1 , or PD-L2.

[0255] In embodiments, the anti-immune checkpoint agent is or comprises an antibody that is capable of binding an immune checkpoint molecule. In embodiments, the antibody is capable of binding programmed cell death protein 1 (PD 1), a PD 1 ligand, and / or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). In embodiments, the antibody is capable of binding PD-1 and is optionally selected from pembrolizumab

[0256] DBl / 161946556.2 45 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0257] (KEYTRUDA), nivolumab (OPDIVO), cemiplimab (LIBTAYO), pidilizumab (CT 011), dostarlimab (JEMPERLI), Spartalizumab (PDR001), RMP1-14, balstilimab (AGEN2034), Vopratelimab (JTX-4014), Camrelizumab (SHR1210), Sintilimab (IBI308), Tislelizumab (BGB-A317), Toripalimab (JS 001), INCMGA00012 (MGA012), AMP-224, and AMP-514.

[0258] In embodiments, the antibody is capable of binding PD-L1 and is optionally selected from atezolizumab (TECENTRIQ), avelumab (BAVENCIO), durvalumab (IMFINZI), KN035, a lymphocyte activation gene-3 (LAG-3, CD223) inhibitor, relatlimab (BMS-986,016), relatlimab (BMS-986,016) in combination with opdualag (nivolumab) (nivolumab and relatlimab-rmbw), and Cosibelimab (CK-301). In embodiments, the antibody is capable of binding CTLA-4 and is optionally Ipilimumab (YERVOY) or Tremelimumab (IMJUDO).

[0259] In various embodiments, the methods described herein are useful in the evaluation of a solid tumor or liquid tumor sample from a subject, or a blood cancer sample from a subject, for example, for evaluating diagnosis, prognosis, and / or response to treatment. In various aspects, the present disclosure comprises evaluating a solid tumor, liquid tumor, or a blood cancer sample from a subject. In various embodiments, the evaluation is selected from diagnosis, prognosis, and response to treatment. In some embodiments, the methods described herein are useful in predicting the aggressiveness of a solid tumor or liquid tumor sample from a subject, or a blood cancer sample from a subject.

[0260] In some embodiments, a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment. In some embodiments, the subject is a human. In various other embodiments, the subject previously diagnosed with or identified as suffering from or having a condition may or may not have undergone treatment for a condition. In other embodiments, a subject can also be one who has not been previously diagnosed as having a condition (i.e., a subject who exhibits one or more risk factors for a condition). A “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.

[0261] In embodiments, the method further comprises selecting a subject for the treatment. In embodiments, the subject is selected for the treatment based on a reduced expression or activity of POGK in a tumor sample compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample. In embodiments, the expression or activity of POGK is assayed by evaluating the presence, absence, or level of expression or activity of POGK protein or an mRNA encoding POGK.

[0262] DBl / 161946556.2 46 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0263] In various aspects, disclosed herein is a method of determining a cancer treatment for a patient, the method comprising: (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and (b) determining a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0264] In various aspects, disclosed herein is a method for selecting a subject for a cancer treatment, the method comprising: (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and (b) selecting the subject for a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0265] In various aspects, disclosed herein is a method of treating cancer, the method comprising: (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and (b) administering to the subject for a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0266] In embodiments, the biological sample is obtained from blood, serum, saliva, plasma, a tissue sample, a fresh tissue sample, frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen.

[0267] In embodiments, the biological sample is a biopsy sample selected from endoscopic biopsy, bone marrow biopsy, endoscopic biopsy (e.g., cystoscopy, bronchoscopy and colonoscopy), needle biopsy (e.g., fine- needle aspiration, core needle biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computerized

[0268] DBl / 161946556.2 47 Attorney Docket No.: BID-014PC / 110304-5014-PC tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy and ultrasound- assisted biopsy), skin biopsy (e.g., shave biopsy, punch biopsy, and incisional biopsy) and surgical biopsy.

[0269] In embodiments, the biological sample comprises a body fluid selected from blood, plasma, serum, lacrimal fluid, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy sample, cell-containing body fluid, free floating nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swab, vaginal swab, oral swab, nasal swab, washing or lavage such as a ductal lavage or broncheoalveolar lavage, aspirate, scraping, bone marrow specimen, tissue biopsy specimen, surgical specimen, feces, other body fluids, secretions, and / or excretions, and / or cells therefrom.

[0270] In embodiments, the evaluating is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, western blotting, in cell western, immunofluorescent staining, ELISA, and fluorescent activating cell sorting (FACS) or a combination thereof.

[0271] In embodiments, the evaluating is performed by contacting the sample with an agent that specifically binds to POGK protein and / or TRIM28 protein.

[0272] In embodiments, the agent that specifically binds to POGK protein and / or TRIM28 protein is an antibody or fragment thereof, optionally wherein the antibody is a recombinant antibody, a monoclonal antibody, a polyclonal antibody, or fragment thereof.

[0273] In embodiments, the evaluating is performed by contacting the sample with an agent that specifically binds to a nucleic acid encoding POGK protein and / or TRI M28 protein. In embodiments, the nucleic acid is mRNA or cDNA. In embodiments, the agent that specifically binds to one or more of the nucleic acids is a nucleic acid primer or probe.

[0274] In embodiments, the POGK therapy is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like inhibitor, an antibody, an antibody-like molecule, a peptide, a peptidomimetic, and a nucleic encoding POGK isoform 1. In embodiments, the POGK therapy is or comprises a nucleic acid encoding POGK isoform 1. In embodiments, the nucleic acid is DNA. In embodiments, the nucleic acid is an expression vector.

[0275] In embodiments, the POGK therapy is or comprises an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA. In embodiments, in a non-limiting approach, the isolated nucleic acid targets the KRAB domain of POGK and suppresses POGK.

[0276] DBl / 161946556.2 48 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0277] In embodiments, the POGK therapy is or comprises an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 2, wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 1 , or optionally wherein the nucleic acid promotes the degradation of mRNA encoding POGK isoform 1 . In embodiments, the nucleic acid is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA (ASO), and a guide RNA (gRNA). In embodiments, the nucleic acid has a sequence that is complementary to and / or identical to at least 10, or at least 12, or at least 14, or at least 16 contiguous nucleotides of an mRNA encoding POGK isoform 2.

[0278] In embodiments, the nucleic acid has a sequence that is complementary to and / or identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 . In embodiments, the nucleic acid has a sequence that is perfectly complementary to and / or perfectly identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 . In embodiments, the nucleic acid has a sequence that is partially complementary to and / or partially identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 .

[0279] In embodiments, the nucleic acid comprises a sugar modification, backbone modification, and / or a base modification. In embodiments, the backbone modification is a phosphorothioate modification. In embodiments, the sugar modification comprises a 2'-O-methy I (2’OMe) and / or 2’-deoxy 2’-fl uoro modification. In embodiments, the base modification comprises pseudouridine, 5’-methylcytidine, N6-methyladenosine, inosine, and / or N7-methylguanosine.

[0280] In embodiments, the POGK therapy is or comprises an inhibitor of pogo transposable element derived with KRAB domain (POGK) and / or TRIM28. In embodiments, the inhibitor is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like inhibitor, an antibody, an antibody-like molecule, a peptide, and a peptidomimetic. In embodiments, the inhibitor reduces the amount or activity of POGK and / or TRIM28.

[0281] In embodiments, the inhibitor reduces the amount or activity of at least one ribosomal protein gene. In embodiments, the ribosomal protein is selected from RPLP1 , RPL11 , RPL13, RPL15, RPL36, RPS16,

[0282] DBl / 161946556.2 49 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0283] RPS28, and RPS29. In embodiments, the inhibitor inhibits the transcription ofone or more of RPL13, RPL15, RPS16, RPS28, and RPS29.

[0284] In embodiments, the cancer is metastatic. In embodiments, the tumor has metastasized to a tissue or an organ.

[0285] In embodiments, the subject is a mammal. In embodiments, the mammal is a human.

[0286] In aspects, disclosed herein is a composition comprising an antisense oligonucleotide, wherein the composition attenuates, weakens, reduces, decreases, or ablates the splicing that results in isoform 2 of POGK, wherein: the antisense oligonucleotide comprises at least one 2'-O-methylation modifications and at least six internal phosphorothioate deoxyribonucleotides; and the antisense oligonucleotide is about 15 to about 20 nucleotides in length.

[0287] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of isoform 1 of POGK, optionally inhibiting splicing of isoform 1 of POGK, to isoform 2 of POGK.

[0288] In embodiments, the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK, optionally splicing of POGK, to isoform 2.

[0289] In embodiments, the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long. In embodiments, the ASO is about 15 to about 20 nucleotides in length. In embodiments, the ASO is about 15 nucleotides in length. In embodiments, the ASO is about 16 nucleotides in length. In embodiments, the ASO is about 17 nucleotides in length. In embodiments, the ASO is about 18 nucleotides in length. In embodiments, the ASO is about 19 nucleotides in length. In embodiments, the ASO is about 20 nucleotides in length.

[0290] In embodiments, the ASO comprises at least one internal phosphorothioate deoxyribonucleotide. In embodiments, the ASO comprises at least two internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least three internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least four internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least five internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least six internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least seven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eight internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least nine internal phosphorothioate deoxyribonucleotides. In

[0291] DBl / 161946556.2 50 Attorney Docket No.: BID-014PC / 110304-5014-PC embodiments, the ASO comprises at least ten internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least eleven internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least twelve internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises at least 8-10 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 8 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 9 internal phosphorothioate deoxyribonucleotides. In embodiments, the ASO comprises 10 internal phosphorothioate deoxyribonucleotides.

[0292] In embodiments, the ASO comprises at least one terminal 2 -O-methylation modification. In embodiments, the ASO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the ASO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the ASO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5. In embodiments, the plurality of 2'-O-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-0-methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 17 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 18 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 19 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 6-20 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 9-15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11-13 residues.

[0293] In embodiments, the ASO comprises two 2'-O-methylation modifications. In embodiments, the ASO comprises three 2'-O-methylation modifications. In embodiments, the ASO comprises four 2'-O-methylation

[0294] DBl / 161946556.2 51 Attorney Docket No.: BID-014PC / 110304-5014-PC modifications. In embodiments, the ASO comprises five 2'-O-methylation modifications. In embodiments, the ASO comprises six 2'-O-methylation modifications. In embodiments, the ASO comprises seven 2'-O- methylation modifications. In embodiments, the ASO comprises eight 2'-0-methylation modifications. In embodiments, the ASO comprises nine 2'-O-methylation modifications. In embodiments, the ASO comprises ten 2'-O-methylation modifications. In embodiments, the ASO comprises eleven 2'-O-methylation modifications. In embodiments, the ASO comprises twelve 2'-O-methylation modifications.

[0295] In embodiments, the ASO comprises the sequence of SEQ ID NOs: 45-144, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0296] In embodiments, the ASO has perfect sequence complementarity to an RNA molecule encoding POGK.

[0297] In embodiments, the ASO is selected from Table 6, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0298] In embodiments, the ASO has partial sequence complementarity to an RNA molecule encoding POGK.

[0299] In aspects, disclosed herein is a composition comprising an splice suppressing oligonucleotide, wherein the composition targets or suppresses the POGK gene or an isoform thereof, wherein: the splice suppressing oligonucleotide comprises at least one 2'-O-methylation modifications; and the splice suppressing oligonucleotide is about 15 to about 16 nucleotides in length.

[0300] In embodiments, the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3 and / or POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof.

[0301] In embodiments, the SSO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK to isoform 2.

[0302] In embodiments, the SSO is about 15 to about 16 nucleotides in length. In embodiments, the SSO is about 15 nucleotides in length. In embodiments, the SSO is about 16 nucleotides in length.

[0303] In embodiments, the SSO comprises at least one terminal 2 -O-methylation modification. In embodiments, the SSO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O- methylation modifications are at a terminal location. In embodiments, the SSO comprises at least a 3’

[0304] DBl / 161946556.2 52 Attorney Docket No.: BID-014PC / 110304-5014-PC terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. In embodiments, the SSO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.

[0305] In embodiments, the plurality of 2'-0-methylation modifications is at least 7 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 9 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 10 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 12 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 13 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 14 residues. In embodiments, the plurality of 2'-O- methylation modifications is at least 15 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 16 residues.

[0306] In embodiments, the plurality of 2'-O-methylation modifications is at least 6-16 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 8-15 residues. In embodiments, the plurality of 2'- O-methylation modifications is at least 10-14 residues. In embodiments, the plurality of 2'-O-methylation modifications is at least 11-13 residues.

[0307] In embodiments, the SSO comprises two 2'-O-methylation modifications. In embodiments, the SSO comprises three 2'-O-methylation modifications. In embodiments, the SSO comprises four 2'-O-methylation modifications. In embodiments, the SSO comprises five 2'-O-methylation modifications. In embodiments, the SSO comprises six 2'-0-methylation modifications. In embodiments, the SSO comprises seven 2'-O- methylation modifications. In embodiments, the SSO comprises eight 2'-O-methylation modifications. In embodiments, the SSO comprises nine 2'-O-methylation modifications. In embodiments, the SSO comprises ten 2'-O-methylation modifications. In embodiments, the SSO comprises eleven 2'-O-methylation modifications. In embodiments, the SSO comprises twelve 2'-O-methylation modifications. In embodiments, the SSO comprises thirteen 2'-O-methylation modifications. In embodiments, the SSO comprises fourteen 2'-O-methylation modifications. In embodiments, the SSO comprises fifteen 2'-O-methylation modifications. In embodiments, the SSO comprises sixteen 2'-O-methylation modifications.

[0308] In embodiments, the SSO comprises at least one locked nucleic acid (LNA). In embodiments, the SSO comprises two LNAs. In embodiments, the SSO comprises three LNAs. In embodiments, the SSO comprises four LNAs. In embodiments, the SSO comprises five LNAs. In embodiments, the SSO comprises six LNAs.

[0309] DBl / 161946556.2 53 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0310] In embodiments, the SSO comprises seven LNAs. In embodiments, the SSO comprises eight LNAs. In embodiments, the SSO comprises nine LNAs. In embodiments, the SSO comprises ten LNAs. In embodiments, the SSO comprises alternating 2'-O-methylation modifications and LNAs.

[0311] In embodiments, the SSO comprises the sequence of SEQ ID NOs: 145-244, or a variant thereof. In embodiments, the variant comprises about 1, or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0312] In embodiments, the SSO has perfect sequence complementarity to an RNA molecule encoding POGK.

[0313] In embodiments, the SSO has partial sequence complementarity to an RNA molecule encoding POGK.

[0314] In embodiments, the SSO is selected from Table 7, or a variant thereof. In embodiments, the variant comprises about 1 , or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0315] Kits

[0316] In aspects, the present disclosure provides a kit comprising a container comprising the composition of any one of the embodiments and / or aspects disclosed herein, the nucleic acid of any one of the embodiments and / or aspects disclosed herein, the viral vector of any one of the embodiments and / or aspects disclosed herein, the lipid nanoparticle of any one of the embodiments and / or aspects disclosed herein, the cell of any one of the embodiments and / or aspects disclosed herein, or the pharmaceutical composition of any one of the embodiments and / or aspects disclosed herein and with instructions for use in modulating and / or modifying a nucleic acid.

[0317] In embodiments, the present disclosure provides kits for carrying out the methods described herein. In embodiments, the kit comprises a composition described herein, a recombinant expression vector, a delivery system, and / or a pharmaceutical composition described herein, optionally further with a reagent for reconstitution and / or dilution.

[0318] It will also be understood that, although the terms first, second, etc., may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first subject could be termed a second subject, and, similarly, a second subject could be termed a first subject, without departing from the scope of the present disclosure. The first subject and the second subject are both subjects, but they are not the same subject. Furthermore, the terms “subject,” “user,” and “patient” are used interchangeably herein.

[0319] DBl / 161946556.2 54 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0320] As used herein, the word “include,” and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features. Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the disclosure, the present technology, or embodiments thereof, may alternatively be described using more limiting terms such as “consisting of’ or “consisting essentially of” the recited ingredients.

[0321] Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials, similar or equivalent to those described herein, can be used in the practice or testing of the present disclosure, the preferred methods and materials are described herein. All publications, patents, and patent publications cited are incorporated by reference herein in their entirety for all purposes.

[0322] This disclosure is further illustrated by the following non-limiting examples.

[0323] EXAMPLES

[0324] Example 1: Global deregulations of POGK expression across human cancer

[0325] The experiments of this example investigated the potential involvement of TEGs in human cancer development. The experiments of this example assessed the expression levels of mRNAs belonging to the “transposable element-derived genes” family in the human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC) database, which included 128 separate mRNAs. Surprisingly, only one gene, pogo transposable element derived with KRAB domain, or POGK, consistently registered as the topaltered transcript in the several cancer cohorts that were probed. Indeed, the experiments found POGK to be the most changed TEG transcript in lung adenocarcinoma (LUAD) (FIG. 7A), lung squamous cell carcinoma (LUSC) (FIG. 7B) and pancreatic adenocarcinoma (PAAD) (FIG. 7C). POGK was also among the most aberrantly expressed TE-derived gene in ovarian cancer (OV) (FIG. 7D), liver hepatocellular carcinoma (LIHC) (FIG. 7E) and prostate adenocarcinoma (PRAD) (FIG. 7F). Specific assessment of POGK expression in the Cancer Genome Atlas (TOGA) curated set of non-redundant studies revealed its widespread deregulation across additional cancer subtypes, such as melanoma or cholangiocarcinoma (FIG. 8A). Strikingly, POGK was most altered in breast cancer (FIG. 8A), an observation that was verified across

[0326] DBl / 161946556.2 55 Attorney Docket No.: BID-014PC / 110304-5014-PC multiple studies (FIG. 8B), including four of the largest breast cancer cohorts in TCGA (21.5-39.5%; FIG. 1A). These data focused the experiments on POGK and prompted investigation on its potential involvement in breast cancer pathogenesis in particular.

[0327] Example 2: Specific depletion of POGK expression in TNBC

[0328] To explore the functions of POGK in breast cancer, the experiments of this example probed its expression levels using immunohistochemistry on tissue microarrays derived from a large number of luminal, HER2, and TNBC specimens (Table 1). These analyses surprisingly showed a significant diminution of POGK levels in breast cancers compared to normal tissues (75% and 50%, respectively; p<0.001 ; FIG. 1 B) with a notable decrease of POGK-positive (POGKP°S) staining in TNBCs versus non-TNBC samples (-30% versus -60%, respectively; p=0.005; FIG. 1C). The experiments verified these observations in metaplastic breast cancer, which belongs to the TNBC subtype, and found that POGK levels, determined by quantitative RT-PCR (qRT- PCR) on laser-captured cancer cells, were about half of those in normal epithelial cells captured from normal reduction mammoplasties (FIG. 1 D). The experiments also found POGK levels to be lower in basal breast cancer cell lines (-80% TNBCs) as compared to luminal cell lines in Hoeflich dataset (FIG. 1 E), in the Cancer Cell Line Encyclopedia (CCLE; FIG. 1 F), and in a qRT-PCR on a series of luminal and TNBC cell lines (FIG. 1G). These results collectively indicated that POGK expression was particularly down-regulated in TNBC.

[0329] Example 3: POGK dramatically inhibits TNBC Growth

[0330] Given the experiments above, there was interest in elucidating the biological functions of POGK in TNBC development. For this purpose, the experiments of this example stably expressed human POGK (NM_017542.5) cDNA in human TNBC cell lines SUM159, MDA-MB-231 and CAL51 cells, which exhibited low endogenous levels of POGK (FIG. 9A, FIG. 9B, and FIG. 9C). Dramatically, POGK was found to cause a -70% reduction in the anchorage-independent growth of these cells in soft-agar (FIG. 2A and FIG. 2B) and significantly compromised their colony-forming abilities in 2D growth conditions (FIG. 10A, FIG. 10B, and FIG. 10C). Importantly, orthotopic implantation of POGK-over-expressing SUM159 cells into triple- immunodeficient NCG mice, which lack functional / mature T, B and NK cells, or in immunodeficient Nu / Nu mice that are devoid of functional / mature T and B cells revealed a striking inability of these cells to grow tumors when compared to controls, measured both in terms of growth kinetics (FIG. 2C and FIG. 2D) or tumor incidence rates (FIG. 10D and FIG. 10E). These observations were reproduced using murine models of TNBC. Here, POGK-over-expression in 4T1 and 4TO7 cells (FIG. 9D) reduced colony formation in anchorage independence by 40-50% (FIG. 2E and FIG. 2F). Furthermore, human POGK inhibited the

[0331] DBl / 161946556.2 56 Attorney Docket No.: BID-014PC / 110304-5014-PC incidence rates of orthotopic 4T1 tumors in immunocompetent BALB / c mice by 30%-60% (FIG. 10F and FIG. 10G) as well as tumor growth rates (FIG. 2G, FIG. 2H, and FIG. 2I). Together, these data depicted growthsuppressive functions for POGK in TNBC.

[0332] Example 4: POGK causes widespread inhibition of ribosomal gene expression

[0333] The observation that POGK inhibited TNBC cell growth in vitro and in both immune-competent and immunocompromised mice highly indicated that its suppressive functions were intrinsic to the cancer cells. With this postulate, and to identify the mechanism-of-action of POGK in TNBC, the experiments of this example performed RNA-Sequencing on SUM159 cells over-expressing POGK as compared to vector-controlharboring counterparts. These analyses led to the identification of 3,908 differentially expressed genes (DEGs) between POGK over-expressing cells and controls, including 1 ,699 up-regulated DEGs (FC > 2, p<0.05) and 2,209 down-regulated genes (FC > 2, p<0.05) (FIG. 3A). To prioritize these hits, these experiments performed gene set enrichment analyses (GSEA) on the DEGs, which interestingly pointed to a strong association of POGK with regulation of protein translation and ribosome biogenesis. Indeed, these experiments found that POGK-up-regulated DEGs negatively correlated with Proteasomal Protein Catabolic and Ribonucleoprotein Complex Biogenesis (FIG. 11A) and negatively correlated with mTOR Signaling Pathway, which regulates cell growth and protein synthesis (FIG. 11 B). Similarly, POGK-down-regulated DEGs positively correlated with Translational Initiation and RNA Catabolic processes (FIG. 11 C) and with Ribosome, which represented the standout pathway (FIG. 3B). Interestingly, while no gene set significantly scored at FDR<25% from POGK-up-regulated DEGs in C2 (6,495 gene sets) or C5 (15,937 gene sets), 61 and 54 gene sets from POGK-down-regulated DEGs were enriched at nominal p value <1 % and FDR <25% from C2 (Table 2) and C5 (Table 3), respectively, and they correlated with Small and Large Ribosomal Subunits in addition to Ribosome gene ontology (FIG. 3C). To validate the notion that POGK repressed ribosome biogenesis, the experiments queried the expression levels of Large and Small ribosomal protein genes (RPL and RPS, respectively) in the RNA-sequencing analyses. In these experiments, it was observed that POGK, in fact, repressed the expression of 45 / 47 RPL genes and 30 / 32 RPS genes (FIG. 3D), indicative of global inhibition in ribosomal biogenesis by POGK. Most importantly, the overwhelming majority of these genes were determined to be essential for cell survival in SUM159, CAL51 , and MDA-MB-231 TNBC cells in DepMap CRISPR gene screening (FIG. 3E). Collectively, these data are consistent with a model in which POGK-mediated inhibition of ribosomal gene expression leads to stunted TNBC cell growth and survival.

[0334] DBl / 161946556.2 57 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0335] Example 5: Critical role for KRAB domain in POGK regulation of growth, ribosomal gene expression, and

[0336] TRIM28 binding

[0337] The experiments of this example proceeded to determine POGK proximal partners in TNBC cells in order to elucidate how it specifically regulated ribosomal biogenesis. In these experiments, a FLAG tag was fused to the COOH-terminus of POGK and expressed in SUM159 cells. Considering that POGK is nuclear (FIG. 12A), FLAG-POGK was immunoprecipitated from nuclear lysates using FLAG antibodies, resolved the immunoprecipitates using polyacrylamide gel electrophoresis (FIG. 12B), and analyzed the cut FLAG-POGK lane by mass spectrometric analyses. These efforts led to the identification of tripartite motif-containing 28 (or TRIM28) as the top potential POGK binding partner (FIG. 4A and Table 4). Indeed, western blotting for TRIM28 on FLAG-POGK pull-downs validated the association of TRIM28 with POGK in SUM159 and additionally in MDA-MB-231 and CAL51 models (FIG. 4C). Conversely, immunoprecipitation of endogenous TRIM28 pulled down endogenous POGK in the same cell models as well (FIG. 4C).

[0338] To determine the specific binding interface of POGK with TRIM28, POGK variants were generated that harbored truncations in its major domains, which include Kruppel associated box (KRAB), Brinker DNA- binding domain (BrkDBD), centromere protein B-type helix-turn-helix domain (CENPB), and the tricarboxylate DDE_1 catalytic transposase domain (FIG. 4D). In these experiments only POGKAKRAB(which lacks the KRAB domain) was found to have deficient binding of TRIM28 in immunoprecipitation experiments (FIG. 4E). Most importantly, unlike wild type POGK, the POGKAKRABvariant was unable to inhibit anchorageindependent growth in SUM159 cells (FIG. 4F) and did not cause global deregulations of RPL / RPS gene expression in TNBC cells (FIG. 13). Altogether, these results suggested that the KRAB domain and its association with TRIM28 were crucial for POGK control of ribosomal gene expression and for its growth regulatory functions.

[0339] Example 6: Direct repression ofRPS16 and RPS29 transcription by POGK inhibits ribosome biogenesis and cell growth in TNBC

[0340] TRIM28 possesses multiple cellular functions, the most prominent of which is its ability to act as a global transcriptional repressor. In doing so, TRIM28 associates with KRAB-containing transcriptional regulators (e. g . , zinc finger proteins or ZNF) and promotes the recruitment of chromatin-silencing complexes (e. g. , SET Domain Bifurcated Histone Lysine Methyltransferase 1 or SETDB1) to designated target genes. With this in view, the experiments of this example hypothesized that nuclear POGK acts as a transcriptional regulator that silences ribosomal genes and accordingly decided to explore its proximal transcriptional targets. For this

[0341] DBl / 161946556.2 58 Attorney Docket No.: BID-014PC / 110304-5014-PC purpose, chromatin-IP on FLAG-POGK in SUM159 cells was performed followed by DNA sequencing (Ch I P- Seq), which revealed >3,500 peaks (FC>1.2-fold, p<0.05). When cross referenced for ribosomal genes from POGK DEG in the same cells, only 8 RPS and RPL candidates were commonly flagged in both approaches: RPLP1 , RPL11 , RPL13, RPL15, RPL36, RPS16, RPS28, and RPS29 (FIG. 5A). To identify which among the eight candidates was co-regulated by TRIM28, a pool of TRIM28 siRNAs were expressed in POGK-over- expressing and control SUM159 cells. While POGK inhibited the transcription of RPL13, RPL15, RPS16, RPS28, and RPS29, it did not affect the expression of RPL11 and RPL38. Furthermore, TRIM28 siRNAs annulled the ability of POGK to inhibit the transcription of RPS16 and RPS29, but they did not rescue POGK- mediated repression of RPL13, RPL15, and RPS28 and for this reason, were excluded from further investigations (FIG. 5B). That POGK regulated RPS16 and RPS29 in a TRIM28-dependent manner was validated in CAL51 cells too (FIG. 5C). Of note, both RPS16 and RPS29 were found to be enriched in breast cancers in general (FIG. 5D) and in TNBC in specific (FIG. 5E), indicative of their important roles in these settings.

[0342] RPLs and RPSs are interconnected, which suggest they exist in hierarchies where critical members exert widespread regulatory effects on all (or most) other members. To examine the possibility that RPS16 and RPS29 served such a role, the experiments of this example conducted GSEA analyses on their associated genes in TCGA-Breast cancer data (METABRIC and Firehose Legacy) (FIG. 14A, FIG. 14B, FIG. 14C, and FIG. 14D) and identified Ribosome Biogenesis, Localization, Constitution, and Subunits among the most enriched. Furthermore, gene expression datasets of breast cancer were explored, along with basal subtypes from TCGA, and found significant positive correlations of RPS16 and RPS29 with >40 RPLs and >28 RPS (FIG. 14E and FIG. 14F). Interestingly, esiRNAs against RPS16 or RPS29 (FIG. 15A) significantly reduced endogenous expression levels of other ribosomal genes (e.g., RPL1, RPL11, RPL13, RPL15, or RPL38; FIG. 15B). Along similar lines, RPS16 or RPS29 knockdown caused 40%-60% reduction in the 2D colony formation abilities of SUM159 (FIG. 5F) and CAL51 (FIG. 5G) cells, and severely (60%-80%) limited their proliferation in 2D cultures (FIG. 5H, FIG. 5I). Importantly, knockdown of RPS16 or RPS29 almost (by 80%- 90%) eliminated SUM159 colony-formation in anchorage-independent soft-agar conditions (FIG. 5J). These results depict essential, leading roles of both RPS proteins in ribosomal gene expression and in TNBC cell growth.

[0343] Example 7: Isoform switching neutralizes POGK growth suppressive functions in TNBC

[0344] DBl / 161946556.2 59 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0345] The experiments of this example investigated how POGK expression becomes downregulated in TNBC. These experiments could not find any overt mutations in POGK DNA (that could potentially inactivate the protein) in the cancer genome in general, in its amino acid makeup, or in BRCA genome in specific (FIG. 16A and FIG. 16B). In addition, no significant alterations in endogenous POGK expression following cancer cell treatment with a DNA methyltransferase (DNMT) inhibitor were observed, indicating that DNA methylation of POGK played little role, if any, in its expression regulation (FIG. 16C). The experiments of this example therefore examined the possibility that POGK was altered at the post-transcriptional level, focusing on POGK isoform differential representations, a common phenomenon in cancer. In fact, POGK is spliced into two main isoforms: a full-length isoform (NM_017542.5; referred to herein as “isoform 1” or “iso1 used throughout our aforementioned over-expression studies) with coding exons 2, 3, 4, and 5, and isoform 2 (NM_001314014.2; referred to herein as “iso2”) that lacks exons 2, 3, and 4 (which code for the KRAB domain) and is coded for by exon 5 (FIG. 6A). Cursory assessments of the expression of these exons across multiple tumors versus their corresponding normal tissues indeed indicated that while exon 5 was almost unchanged, exons 2-4 were dramatically reduced (FIG. 6B). When examined more closely, iso1 and iso 2 exhibited significant, negative correlation indices (r=-0.207 to -0.443; p<0.05) in breast cancer, pancreatic adenocarcinoma, liver hepatocellular carcinoma, prostate adenocarcinoma, and more importantly, in TNBC (FIG. 6C and FIG. 6D), consistent with isoform switching of POGK in the neoplastic setting. To empirically test these notions in TNBC, qRT-PCR was conducted on iso1 and iso2 in laser-captured TNBC cells versus controls (FIG. 6D) and found a 3.5-fold increase in the ratio of iso2 / iso1 in metaplastic tumors with only a slight, but significant increase, in iso2 (FIG. 6E). Of pertinence, while doxycycline (DOX)-inducible expression of full length POGK (iso1 ; FIG. 9E) in mammary-fat-pad-imbedded-4T1 cells led to significant diminution of the growth kinetics and of the Ki67-positivity of these tumors in syngeneic BALB / c mice (DOX started at day 12; FIG. 6F and FIG. 6G), no effect was observed when POGK iso2 was induced in similar settings (FIG. 6H). These observations indeed mirrored earlier observations in which POGK missing the KRAB domain was inactive in growth suppression of SUM159 cells in vitro (FIG. 4F). Finally, whereas POGK iso1 inhibited mouse Rps16 and Rps29 in 4T1 tumors (FIG. 6I) and negatively correlated with both RPS16 and RPS29 in clinical TNBC (r=-0.4; p<0.001; FIG. 6J), iso2 did not affect Rps16 or Rps29 (FIG. 6K) and was in effect positively associated with RPS16 and RPS29 in the same clinical specimens (FIG. 6I). In total, these data are consistent with the premise that exon skipping reduces POGK iso1 expression and circumvents its growth inhibitory functions in TNBC.

[0346] DBl / 161946556.2 60 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0347] FIG. 17A FIG. 17B, FIG. 17C, FIG. 17D, FIG. 17E and FIG. 17F are graphs showing the use of POGK to stratify patients with the worst outcome. FIG. 17A, FIG. 17B, FIG. 17C, FIG. 17D, FIG. 17E and FIG. 17F show POGK representing a biomarker, and indicate that POGK-low TNBC tumors give patients poorer survival than POGK-high tumors. This applies to patients whose disease went to the lymph nodes.

[0348] FIG. 18A, FIG. 18B, FIG. 18C, and FIG. 18D are images and graphs showing knockout of POGK induces cellular senescence in TNBC cells. FIG. 19A and FIG. 19B are images and graphs showing a POGK CRISPR-pool that inhibits MDA-MB-468 cell growth. FIG. 20A and FIG. 20B are graphs showing knockdown of POGK by shRNA inhibits cell growth in human TNBC cells. FIG. 21 A, FIG. 21 B, FIG. 21 C, FIG. 21 D, and FIG. 21 E are images and graphs showing knockdown of POGK by shRNA inhibits cell growth in mouse TNBC cells.

[0349] FIG. 22A, FIG. 22B, FIG. 22C, and FIG. 22D are images and graphs showing how POGK ASOs induce TNBCs cell death. FIG. 22A shows qRT-PCR experiments of POGK in CAL51 cells following 48-hour treatment with NC1 ASO or POGK ASOs #1-25 at 100 nM, which correspond to the following SEQ IDs: ASO1 (SEQ ID NO: 1), ASO2 (SEQ ID NO: 2), ASO3 (SEQ ID NO: 3), ASO4 (SEQ ID NO: 4), ASO5 (SEQ ID NO: 5), ASO6 (SEQ ID NO: 6), ASO7 (SEQ ID NO: 7), ASO8 (SEQ ID NO: 8), ASO9 (SEQ ID NO: 9), ASO10 (SEQ ID NO: 10), ASO11 (SEQ ID NO: 11), ASO12 (SEQ ID NO: 12), ASO13 (SEQ ID NO: 13), ASO14

[0350] (SEQ ID NO: 14), ASO15 (SEQ ID NO: 15), ASO16 (SEQ ID NO: 16), ASO17 (SEQ ID NO: 17), ASO18

[0351] (SEQ ID NO: 18), ASO19 (SEQ ID NO: 19), ASO20 (SEQ ID NO: 20), ASO21 (SEQ ID NO: 21), ASO22

[0352] (SEQ ID NO: 22), ASO23 (SEQ ID NO: 23), ASO24 (SEQ ID NO: 24) and ASO25 (SEQ ID NO: 25). FIG.

[0353] 22B shows western blot experiments in CAL51 cells following 48-hour treatment with NC1 ASO or POGK ASOs (#4, #20, #21) at 100 nM. POGK ASOs #4, #20, #21 correspond to the following SEQ IDs: ASO4 (SEQ ID NO: 4), ASO20 (SEQ ID NO: 20), and ASO21 (SEQ ID NO: 21). FIG. 22C shows apoptosis cell ratio experiments of CAL51 cells following 48-hour treatment with NC1 ASO or POGK ASOs (#4, #20, #21) at 100 nM. POGK ASOs #4, #20, #21 correspond to the following SEQ IDs: ASO4 (SEQ ID NO: 4), ASO20 (SEQ ID NO: 20), and ASO21 (SEQ ID NO: 21). FIG. 22D shows qRT-PCR experiments of POGK in MDA- MB-468 cells following 48-hour treatment with NC1 ASO or POGK ASOs (#4, #20, #21) at 100 nM. POGK ASOs #4, #20, #21 correspond to the following SEQ IDs: ASO4 (SEQ ID NO: 4), ASO20 (SEQ ID NO: 20), and ASO21 (SEQ ID NO: 21).

[0354] DBl / 161946556.2 61 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0355] FIG. 23A and FIG. 23B are graphs showing how POGK SSOs inhibit TNBCs cellular growth. FIG. 23A shows cell growth ratio experiments of CAL51 cells treated with NC or POGK SSO1 (SEQ ID NO: 145), SSO2 (SEQ ID NO: 146), SSO3 (SEQ ID NO: 147), SSO4 (SEQ ID NO: 148), SSO5 (SEQ ID NO: 149), or SSO6 (SEQ ID NO: 150) at 100 nM, measured on day 4 relative to day 1 using WST-1 assay. FIG. 23B shows cell growth ratio experiments of CAL51 cells treated with NC or POGK SSO4 (SEQ ID NO: 148), at 100 nM, measured on day 4 relative to day 1 using WST-1 assay.

[0356] Collectively, the results shown in these experiments and examples demonstrate, inter alia, that systematic analyses of TEG expression across human cancer reveals a prominent role for pogo transposable element derived with KRAB domain (POGK). The experiments described herein show, inter alia, that POGK acts as a tumor suppressor in triple-negative breast cancer (TNBC) and that it couples with the co-repressor TRIM28 to directly block the transcription of ribosomal genes RPS16 and RPS29, in turn causing widespread inhibition of ribosomal biogenesis. These experiments demonstrate, inter alia, that POGK is deactivated by isoform switching in clinical TNBC, altogether revealing its previously undescribed, exapted activities in tumor growth control.

[0357] Methods

[0358] Tumorigenesis assays

[0359] All mouse work was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at Beth Israel Deaconess Medical Center and Harvard Medical School (protocol numbers: 061-2016 and 083- 2021). Six-week-old female Nu / Nu mice, NCG mice (NOD-Prkdcem26Cd52IL2rgem26Cd22 / NjuCrl Coisogenic Immunodeficient), or BALB / c mice (Charles River, MA) were maintained in accordance with the IACUC recommendations for care, welfare, and treatment of laboratory animals. All experiments met the standards of the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC), the United States Department of Health and Human Services, and all local and federal animal welfare laws. For tumorigenesis assays, Nu / Nu, NCG mice, or BALB / c mice were injected with 2.5x105cells in mammary fat pad. For the DOX-inducible POGK experiment, POGK isoform 1 cells (2.5x105) or POGK isoform 2 cells (1 x 105) were injected into BALB / c mice mammary fat pad and DOX (2 mg / ml in drinking water supplemented with 1 % sucrose) was started at days 11-12. Fresh DOX / water was replaced every 3 days. Mice were sacrificed at the endpoint and the tumors were excised for further experiments. The tumor volume was calculated according to the equation Volume = (W2x L) / 2. Tumor volume and weight were determined.

[0360] DBl / 161946556.2 62 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0361] Cell culture

[0362] Cell lines MDA-MB-231, MDA-MB-468, BT549 and HEK293T cells were purchased from American Type Culture Collection (ATCC, Manassas, VA). SUM159, BT474, SK-BR-3, T47D, MDA-MB-361 , AU565, MDA- MB-453, ZR-75-1 and CAL51 cells were kindly provided by A. Toker (Beth Israel Deaconess Medical Center, Boston, MA). MCF7, 4T1 and 4TO7 cells were kindly provided by R. Weinberg (Whitehead Institute, Cambridge, USA). SUM159 line was cultured in Ham’s F12 medium with 5% FBS, 5 pg / ml Insulin and 1 pg / ml Hydrocortisone. Other cells were cultured according to ATCC recommendations. For viral transduction, HEK293T cells (pre-treated with 25 pM chloroquine diphosphate for 5 hrs) were co-transfected with transfer plasmid, pMD2.G (12259, Addgene, Watertown, MA) and psPAX2 (12260, Addgene, Watertown, MA) using Polyethylenimine (MW 25000) (Polysciences, Warrington, PA). Lentiviral supernatants were collected after 48-72 hrs, filtered, and particles used to infect target cells in the presence of polybrene (10 pg / ml; Santa Cruz Biotechnology, Dallas, TX). Stable cell lines selected in Puromycin (2 pg / ml; Wisent Bioproducts, Quebec, Canada).

[0363] Constructs and siRNAs

[0364] POGK and POGKAKRABcDNA sequences were amplified from MDA-MB-231 cells (for primer sequences, see Table 5) and inserted into pLVX plasmid (provided by P. Pandolfi, Beth Israel Deaconess Medical Center, Boston, MA) using Gibson assembly tool by using the Smal restriction site. POGK was also subcloned into pCW57-GFP-2A-MCS (71783, Addgene, Watertown, MA) using the BamHI restriction site. FLAG sequence was inserted into 3’ pLVX-POGK by using QuikChange kit (200555) (for primer sequences, see Table 5) according to manufacturer’s instructions (Agilent, Santa Clara, CA). Deletion of POGK fragments was performed by PCR based on pLVX-FLAG-POGK plasmid using primers (see Table 5) for POGKABrkDBD, POGKACENPBand POGKADDE-1. The esiRNA for RLUC (EHURLUC), TRIM28 (EHU067331), RPS16 (EHU106041) and RPS29 (EHU117201) were obtained from Millipore Sigma (St. Louis, MO).

[0365] Computational analyses

[0366] MRNA alterations of 128 TEGs (minus ERVH-8, ERVH-9, and ERVH-10 for lack of associated data) were downloaded from cbioportal (on the World Wide Web (www) at cbioportal.org / ), which include Breast Invasive Cancer cohort 1 (Firehose Legacy, 1 ,100 samples), cohort 2 (PanCancer Atlas, 1 ,082 samples), cohort 3 (Cell 2015, 817 samples) and cohort 4 (Nature 2012, 526 samples), Lung Adenocarcinoma (Firehose Legacy, 517 samples; PanCancer Atlas, 510 samples), Lung Squamous cell carcinoma (Firehose Legacy, 501 samples; PanCancer Atlas, 484 samples), Pancreatic Adenocarcinoma (Firehose Legacy, 179 samples;

[0367] DBl / 161946556.2 63 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0368] PanCancer, 177 samples), Ovarian Serous Cystadenocarcinoma (Firehose Legacy, 307 samples; PanCancer Atlas, 300 samples), Liver Hepatocellular Carcinoma (Firehose Legacy, 373 samples; PanCancer, 366 samples) and Prostate Adenocarcinoma (Firehose Legacy, 498 samples; PanCancer Atlas, 493 samples). Total of 67,643 samples from Curated set of non-redundant studies (on the World Wide Web (www) at cbioportal.org / ) were used for exploring POGK Copy number alterations (CNA) status (altered cases > 5%), and 11 ,253 samples from Curated set of non-redundant breast studies (on the World Wide Web (www) at cbioportal.org / ) were used for exploring POGK CNA status in breast (altered cases >2.5%). Hoeflich and CCLE cell line expression data were downloaded from R2 platform ((on the World Wide Web (www) at hgserver1.amc.nl / cgi-bin / r2 / main.cgi). POGK expression data after DNMT inhibitor treatment were downloaded from GEO database (on the World Wide Web (www) at ncbi.nlm.nih.gov / geo / ). The estimated knockout effect scores were downloaded from Depmap (CRISPR gene effect 22Q2, (on the World Wide Web (www) at depmap.org / portal / ). Correlation analyses between POGK and RPS16, RPS29 were downloaded from TSVdb database (on the World Wide Web (www) at tsvdb.com / plot.html). RPS16 and RPS29 protein expression data were downloaded from UALCAN (on the World Wide Web (www) at ualcan.path.uab.edu / index.html). POGK mutation status determination was performed by COSMIC data ( on the World Wide Web (www) at cancer.sanger.ac.uk / cosmic) and GDC ( on the World Wide Web (www) at portal.gdc.cancer.gov / exploration). Gene Set Enrichment Analysis (GSEA) was performed by GSEA 4.2.3 ( on the World Wide Web (www) at gsea-msigdb.org / gsea / index.jsp) and was used to identify set of genes that associated with RPS16 or RPS29 -positively correlated genes or with differentially expressed genes from RNA Seq data. The criteria for significantly enriched gene sets included nominal p-value (< 5%) and false discovery rate (< 25%). qPCR determinations

[0369] Gene expression was determined using RT-qPCR on total cellular RNA extracted using RNeasy (Qiagen, Hilden, Germany) and assessed using NanoDrop ND-1000 (Thermo Scientific, Rockford, IL). First strand synthesis was performed on equilibrated RNA (2 g) using high-capacity cDNA reverse transcription kit (4368814, Applied Biosystems, Waltham, MA), and cDNA was amplified by PowerUp™ SYBR™ Green Master Mix (A25742, Applied Biosystems, Waltham, MA) in CFX384 cycler (Bio-Rad, Hercules, CA). Abundance of mRNA was determined using the 2A-AACtmethod and normalized to 18S. Primers used are listed in Table 5.

[0370] Clinical samples

[0371] DBl / 161946556.2 64 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0372] RNA derived from clinical breast cancer specimens or from reduction mammoplasty tissues were prepared from laser-captured material processed using RNeasy (Qiagen, Hilden, Germany) and collected under a Curie Institute (Paris, France) institutional review board (IRB) protocol.

[0373] Immunohistochemistry (IHC)

[0374] IHC was performed using standard techniques. Estimation of POGK (HPA031630, Millipore Sigma, St. Louis, MO) positivity in breast tissue microarray (BC081116e, BR1191 and BRN801c from US Biomax, Derwood, MD) and estimation of Ki-67 positivity in 4T1 -burden BALB / c mice tissues were conducted in a blinded fashion by a trained pathologist (L. Quintana) under microscopy at *200 magnification.

[0375] Cellular growth assays

[0376] For proliferation assays, a total of 5.0*103cells were seeded per well in 96-well plate and growth was measured using WST-1 kit (11644807001 , Millipore Sigma, St. Louis, MO) according to the manufacturer’s instructions. Alternatively, a total of 0.5x104or 3.0*104cells were plated per well in 12-well plates and growth was measured by counting the cell numbers at indicated time points using Trypan blue exclusion assay. For colony formation assay, a total of 500 cells were seeded in 6-well plates in complete medium. Cells were fixed by 4% paraformaldehyde (PFA) and stained by 0.2% crystal violet after ~1-2 weeks and counted using Image J software (NIH Image, Bethesda, MD). For anchorage-independent growth assay, suspended cells were mixed with equal volume of 0.35% agar and seeded into 6-well plates pre-coated with 0.625% agar at a density of 2.0-5.0* 103cells per well. Colonies were visualized ~2-6 weeks later using microscopy, stained with 0.002 % Crystal Violet, imaged, and colony numbers counted with Image J software (NIH Image, Bethesda, MD). For doxycycline (DOX)-inducible cells, DOX (1 pg / ml) were added every two days.

[0377] Western blot analyses

[0378] Western blot analysis was performed using standard techniques with antibodies recognizing POGK (sc- 515752, Santa Cruz, Dallas, TX), TRIM28 (ABE1859, Millipore Sigma, St. Louis, MO), FLAG (F1804, Millipore Sigma, St. Louis, MO), GAPDH (2118, CST), and Vinculin (4650, CST).

[0379] Immunofluorescence staining

[0380] Cells (5.0*104) were cultured in one well of 4-chamber polystyrene tissue culture vessel treated glass slide (354104, Corning, Corning, NY) and incubated at 4°C overnight. Cells were then fixed in 4% paraformaldehyde solution for 30 mins at RT, permeabilized with 0.5% Triton X-100 and 0.5% BSA in PBS at 37°C for 30 mins, washed with PBS for 10 mins at RT, blocked with 10% Goat serum and 1 % BSA for 30

[0381] DBl / 161946556.2 65 Attorney Docket No.: BID-014PC / 110304-5014-PC mins at RT, and then incubated with anti-FLAG (F1804, Millipore Sigma, St. Louis, MO) antibody in 1.5% normal blocking serum in PBS for over-night in the dark (ratio 1 :1000). Slides were then incubated with the secondary antibody in 1 .5% normal blocking serum in PBS for 45 mins in the dark. Slides were then treated with mounting media with nuclear stain for visualization.

[0382] Immunoprecipitation (IP)

[0383] IP was performed using standard techniques. Typically, cells were lysed by EBC lysis buffer (20 mM Tris HCL(pH 8.0), 1 % NP40, 120 mM NaCI, 2 mM EDTA) supplemented with EDTA-free Halt Protease and Phosphatase Inhibitor Cocktail (Thermo Scientific, Rockford, IL), and the lysates incubated with the precleared magnetic anti-FLAG beads (M8823, Millipore Sigma, St. Louis, MO) or antibody-beads mixture (anti- TRIM28 (ABE-1859, Millipore Sigma, St. Louis, MO) and Protein G Plus / Protein A Agarose beads (IP05, Millipore Sigma, St. Louis, MO)) were rotated overnight at 4°C. Beads were then washed for more than 5 times by NETN washing buffer (20 mM Tris HCL (pH 8.0), 0.5% NP40, 100 mM NaCI, 1 mM EDTA). Finally, beads were boiled in 1X SOS loading buffer for 10 mins at 95°C, and the IP substrates processed for silver staining, Coomassie staining, mass spectrometry (Taplin Mass Spectrometry Facility, Harvard Medical School, Boston, MA) or Western Blot verification.

[0384] RNA-Sequencing

[0385] Total cellular RNA was extracted using RNEasy (Qiagen, Hilden, Germany) and assessed using NanoDrop ND-1000 (Thermo Fisher Scientific, Waltham, MA). Total of 100 ng RNA was further processed for ribosomal RNA removal using the Epicenter rRNA depletion kit. Ribosomal RNA-depleted samples were subsequently used to generate paired-end sequencing libraries using the Illumina RNA TruSeq Library Kit. Quantity and quality of RNA-Seq libraries were analyzed by Qubit and Agilent Bioanalyzer, respectively, and the libraries were pooled at a final concentration of 12 pM and sequenced by HiSeq SR50. All processes were according to the manufacturer’s instructions. RNA Seq was performed in Whitehead Institute for Biomedical Research Genome Technology Core (Cambridge, MA).

[0386] ChlP-Sequencing

[0387] Culture plates (5.0* 106cells) were treated with 16% methanol-free formaldehyde (1 % of the total volume in serum free medium) and rotated for 10 mins at room temperature. Glycine was subsequently added to stop the crosslinking process. The pellet was resuspended in 150 pl SDS lysis buffer (1 % SDS, 10 mM EDTA, 50 mM Tris-HCL pH 8.0, protease inhibitor cocktail) and nuclear lysates sonicated for 15s on and 45s off for 72

[0388] DBl / 161946556.2 66 Attorney Docket No.: BID-014PC / 110304-5014-PC cycles. The sonicates were then collected and incubated with anti-POGK, anti-FLAG or mouse IgG antibodies and Protein G Plus / Protein A Agarose beads (IP05, Millipore Sigma, St. Louis, MO) overnight under rotation at 4°C. The mixtures were then pelleted, washed once by low salt immune complex wash buffer (0.1 % SDS, 1 % Triton-X-100, 2 mM EDTA, 20 mM Tris-HCL pH 8.0, 150 mM NaCI), high salt immune complex wash buffer (0.1% SDS, 1% Triton-X-100, 2 mM EDTA, 20 mM Tris-HCL pH 8.0, 500 mM NaCI), LiCI immune complex wash buffer (0.25 M LiCI, 1 % NP-40, 1 % Deoxycholate, 1 mM EDTA, 10 mM Tris-HCL pH 8.0) and washed then twice with TE buffer (1 mM EDTA, 10 mM Tris-HCL(pH 8.0)). The precipitates were then resuspended in ChIP dilution buffer (1 % Triton-X-100, 1 mM EDTA, 20 mM Tris-HCL pH 8.0, 150 mM NaCI) and then treated with 20 mg / ml Protease K and 200 nM NaCI at 65°C overnight for protein digestion. Finally, recovered the DNA was recovered using Qiagen PCR purification kit. ChlP-seq was performed by Azenta NGS laboratory (Waltham, MA).

[0389] Statistical analysis

[0390] Results were expressed as means ± sem and data were analyzed using unpaired two-tailed t test unless otherwise noted. Pearson’s Chi-square test was used to analyze the association between the expression of POGK and the clinicopathological characteristics. Correlation analyses were performed using Bivariate Pearson correlation (SPSS: version 23). For all analyses, *, **, *** and **** indicated p<0.05, p<0.01 , p<0.001 and p<0.0001 , respectively.

[0391] Data availability

[0392] Public RNA-seq for TCGA dataset were downloaded from cbioportal (on the World Wide Web (www) at cbioportal.org). Public RNAseq data about Hoeflich and CCLE data were downloaded from R2 platform (on the World Wide Web (www) at hgserver1.amc.nl / cgi-bin / r2 / main.cgi). RPS16 and RPS29 protein expression data were downloaded from UALCAN (on the World Wide Web (www) at ualcan.path.uab.edu). POGK and RPS16, RPS29 isoform expression data were downloaded from TSVdb database (on the World Wide Web (www) at tsvdb.com). The estimated knockout effect scores were downloaded from Depmap (CRISPR gene effect 22Q2, on the World Wide Web (www) at depmap.org).

[0393] Table 1 : The relationship between POGK expression and clinicopathological features in clinical normal breast and breast cancer specimens.

[0394] DBl / 161946556.2 67 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0395] DB1 / 161946556.2 68 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0396] Table 2. GSEA report for POGK down-regulated DEGs (C2 gene sets’

[0397] DBl / 161946556.2 69 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0398] DB1 / 161946556.2 70 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0399] DB1 / 161946556.2 71 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0400] Table 3. GSEA report for POGK down-regulated DEGs (C5 gene sets;

[0401] DBl / 161946556.2 72 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0402] DB1 / 161946556.2 73 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0403] Table 4. The potential binding targets of POGK identified by Mass Spectrometry

[0404] DBl / 161946556.2 74 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0405] DB1 / 161946556.2 75 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0406] DB1 / 161946556.2 76 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0407] DB1 / 161946556.2 77 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0408] DB1 / 161946556.2 78 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0409] DB1 / 161946556.2 79 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0410] DB1 / 161946556.2 80 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0411] DB1 / 161946556.2 81 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0412] DB1 / 161946556.2 82 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0413] DB1 / 161946556.2 83 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0414] DB1 / 161946556.2 84 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0415] DB1 / 161946556.2 85 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0416] DB1 / 161946556.2 86 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0417] DB1 / 161946556.2 87 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0418] DB1 / 161946556.2 88 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0419] Table 5. The Oligonucleotide sequence list

[0420] DBl / 161946556.2 89 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0421] DB1 / 161946556.2 90 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0422] Table 6: Antisense Oligonucleotide (ASO) sequences

[0423] DBl / 161946556.2 91 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0424] DB1 / 161946556.2 92 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0425] DB1 / 161946556.2 93 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0426] Table 7: Splice Suppressing Oligonucleotide (SSO) sequences

[0427] DBl / 161946556.2 94 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0428] DB1 / 161946556.2 95 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0429] EMBODIMENTS

[0430] Various additional embodiments of the disclosure are provided by the following enumerated embodiments, which can be combined in any number and in any combination. Embodiment 1 . A method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 , or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid encoding a pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject. Embodiment 2. The method of embodiment 1 , wherein the nucleic acid is DNA.

[0431] DB1 / 161946556.2 96 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0432] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the nucleic acid is an expression vector.

[0433] Embodiment 4. The method of embodiment 3, wherein the expression vector is a viral vector.

[0434] Embodiment 5. The method of embodiment 4, wherein the viral vector is selected from a lentivirus vector (LV) a retrovirus vector (RV), an adenovirus vector (AV), an adeno-associated virus vector (AAV), and an a virus vector (e.g., a Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV) vector).

[0435] Embodiment 6. The method of embodiment 1 , wherein the nucleic acid is mRNA.

[0436] Embodiment 7. The method of embodiment 6, wherein the nucleic acid is a modified mRNA (mmRNA).

[0437] Embodiment 8. The method of embodiment 7, wherein the mmRNA comprises at least one modified nucleotide selected from pseudouridine (1), N1 -methyl-pseudouridine, N6-methyladenosine (m6A), N1- methyladenosine (ml A), 5-methylcytosine (m5C), and 5-hydroxymethylcytosine (hm5C).

[0438] Embodiment 9. The method of embodiment 7 or embodiment 8, wherein the mmRNA further comprises 5’ untranslated region (5’-UTR), and 3’ untranslated region (3’-UTR), 5' cap structure and / or 3’-poly(A) tail.

[0439] Embodiment 1O.The method of any one of embodiments 1 to 9, wherein the nucleic acid is formulated as a lipid nanoparticle (LNP), a lipoplex, or a liposome.

[0440] Embodiment 11 .A method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA and administering the cell to the subject.

[0441] Embodiment 12.The method of embodiment 11 , wherein the nucleic acid is an antisense oligonucleotide (ASO).

[0442] Embodiment 13. The method of embodiment 12, wherein the ASO inhibits the formation of mRNA encoding POGK isoform 2, and / or the ASO inhibits the formation of mRNA encoding POGK isoform 1 , and / or promotes the formation of mRNA encoding POGK isoform 1 .

[0443] DBl / 161946556.2 97 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0444] Embodiment 14.The method of embodiment 12 or embodiment 13, wherein the ASO promotes the inclusion of exon 2 of POGK in the mRNA, optionally wherein the ASO promotes the formation of an mRNA comprising exons 2, 3, 4, 5, and 6.

[0445] Embodiment 15.The method of any one of embodiments 1 to 14, wherein the isolated nucleic acid targets the KRAB domain of POGK and suppresses POGK.

[0446] Embodiment 16.The method of any one of embodiments 12-15, wherein the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of isoform 1 of POGK, optionally inhibiting splicing of isoform 1 of POGK to isoform 2 of POGK.

[0447] Embodiment 17.The method of any one of embodiments 12-15, wherein the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK, optionally splicing of POGK to isoform 2.

[0448] Embodiment 18.The method of any one of embodiments 12 to 17, wherein the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long.

[0449] Embodiment 19.The method of any one of embodiments 12-18, wherein the ASO is about 15 to about 20 nucleotides in length.

[0450] Embodiment 2O.The method of any one of embodiments 12-19, wherein the ASO is about 15 nucleotides in length.

[0451] Embodiment 21 .The method of any one of embodiments 12-19, wherein the ASO is about 16 nucleotides in length.

[0452] Embodiment 22.The method of any one of embodiments 12-19, wherein the ASO is about 17 nucleotides in length.

[0453] Embodiment 23.The method of any one of embodiments 12-19, wherein the ASO is about 18 nucleotides in length.

[0454] Embodiment 24.The method of any one of embodiments 12-19, wherein the ASO is about 19 nucleotides in length.

[0455] Embodiment 25.The method of any one of embodiments 12-19, wherein the ASO is about 20 nucleotides in length.

[0456] Embodiment 26.The method of any one of embodiments 12-25, wherein the ASO comprises at least one internal phosphorothioate deoxyribonucleotide.

[0457] DBl / 161946556.2 98 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0458] Embodiment 27.The method of any one of embodiments 12-26, wherein the ASO comprises at least two internal phosphorothioate deoxyribonucleotides.

[0459] Embodiment 28.The method of any one of embodiments 12-27, wherein the ASO comprises at least three internal phosphorothioate deoxyribonucleotides.

[0460] Embodiment 29.The method of any one of embodiments 12-28, wherein the ASO comprises at least four internal phosphorothioate deoxyribonucleotides.

[0461] Embodiment 3O.The method of any one of embodiments 12-29, wherein the ASO comprises at least five internal phosphorothioate deoxyribonucleotides.

[0462] Embodiment 31 .The method of any one of embodiments 12-30, wherein the ASO comprises at least six internal phosphorothioate deoxyribonucleotides.

[0463] Embodiment 32.The method of any one of embodiments 12-31 , wherein the ASO comprises at least seven internal phosphorothioate deoxyribonucleotides.

[0464] Embodiment 33.The method of any one of embodiments 12-32, wherein the ASO comprises at least eight internal phosphorothioate deoxyribonucleotides.

[0465] Embodiment 34.The method of any one of embodiments 12-33, wherein the ASO comprises at least nine internal phosphorothioate deoxyribonucleotides.

[0466] Embodiment 35.The method of any one of embodiments 12-34, wherein the ASO comprises at least ten internal phosphorothioate deoxyribonucleotides.

[0467] Embodiment 36.The method of any one of embodiments 12-35, wherein the ASO comprises at least eleven internal phosphorothioate deoxyribonucleotides.

[0468] Embodiment 37.The method of any one of embodiments 12-36, wherein the ASO comprises at least twelve internal phosphorothioate deoxyribonucleotides.

[0469] Embodiment 38.The method of any one of embodiments 12-37, wherein the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides.

[0470] Embodiment 39.The method of any one of embodiments 12-38, wherein the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides.

[0471] DBl / 161946556.2 99 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0472] Embodiment 4O.The method of any one of embodiments 12-39, wherein the ASO comprises at least 8-10 internal phosphorothioate deoxyribonucleotides.

[0473] Embodiment 41 .The method of any one of embodiments 12-40, wherein the ASO comprises 8 internal phosphorothioate deoxyribonucleotides.

[0474] Embodiment 42.The method of any one of embodiments 12-41, wherein the ASO comprises 9 internal phosphorothioate deoxyribonucleotides.

[0475] Embodiment 43.The method of any one of embodiments 12-42, wherein the ASO comprises 10 internal phosphorothioate deoxyribonucleotides.

[0476] Embodiment 44.The method of any one of embodiments 12-43, wherein the ASO comprises at least one terminal 2’-O-methylation modification.

[0477] Embodiment 45.The method of any one of embodiments 12-44, wherein the ASO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O-methylation modifications are at a terminal location.

[0478] Embodiment 46.The method of any one of embodiments 12-45, wherein the ASO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5.

[0479] Embodiment 47.The method of any one of embodiments 12-46, wherein the ASO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5.

[0480] Embodiment 48.The method of any one of embodiments 12-47, wherein the plurality of 2'-O-methylation modifications is at least 7 residues.

[0481] Embodiment 49.The method of any one of embodiments 12-48, wherein the plurality of 2'-O-methylation modifications is at least 8 residues.

[0482] Embodiment 5O.The method of any one of embodiments 12-49, wherein the plurality of 2'-O-methylation modifications is at least 9 residues.

[0483] Embodiment 51 .The method of any one of embodiments 12-50, wherein the plurality of 2'-O-methylation modifications is at least 10 residues.

[0484] Embodiment 52.The method of any one of embodiments 12-51 , wherein the plurality of 2'-O-methylation modifications is at least 11 residues.

[0485] DBl / 161946556.2 100 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0486] Embodiment 53.The method of any one of embodiments 12-52, wherein the plurality of 2'-O-methylation modifications is at least 12 residues.

[0487] Embodiment 54.The method of any one of embodiments 12-53, wherein the plurality of 2'-O-methylation modifications is at least 13 residues.

[0488] Embodiment 55.The method of any one of embodiments 12-54, wherein the plurality of 2'-O-methylation modifications is at least 14 residues.

[0489] Embodiment 56.The method of any one of embodiments 12-55, wherein the plurality of 2'-O-methylation modifications is at least 15 residues.

[0490] Embodiment 57.The method of any one of embodiments 12-56, wherein the plurality of 2 -O-methylation modifications is at least 16 residues.

[0491] Embodiment 58.The method of any one of embodiments 12-57, wherein the plurality of 2'-O-methylation modifications is at least 17 residues.

[0492] Embodiment 59.The method of any one of embodiments 12-58, wherein the plurality of 2'-O-methylation modifications is at least 18 residues.

[0493] Embodiment 6O.The method of any one of embodiments 12-59, wherein the plurality of 2'-O-methylation modifications is at least 19 residues.

[0494] Embodiment 61 .The method of any one of embodiments 12-60, wherein the plurality of 2'-O-methylation modifications is at least 6-20 residues.

[0495] Embodiment 62.The method of any one of embodiments 12-61 , wherein the plurality of 2'-O-methylation modifications is at least 9-15 residues.

[0496] Embodiment 63.The method of any one of embodiments 12-62, wherein the plurality of 2'-O-methylation modifications is at least 10-14 residues.

[0497] Embodiment 64.The method of any one of embodiments 12-63, wherein the plurality of 2'-O-methylation modifications is at least 11-13 residues.

[0498] Embodiment 65.The method of any one of embodiments 12-64, wherein the ASO comprises two 2'-O- methylation modifications.

[0499] DBl / 161946556.2 101 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0500] Embodiment 66.The method of any one of embodiments 12-64, wherein the ASO comprises three 2'-O- methylation modifications.

[0501] Embodiment 67.The method of any one of embodiments 12-64, wherein the ASO comprises four 2'-O- methylation modifications.

[0502] Embodiment 68.The method of any one of embodiments 12-64, wherein the ASO comprises five 2'-O- methylation modifications.

[0503] Embodiment 69.The method of any one of embodiments 12-64, wherein the ASO comprises six 2'-O- methylation modifications.

[0504] Embodiment 7O.The method of any one of embodiments 12-64, wherein the ASO comprises seven 2 -0- methylation modifications.

[0505] Embodiment 71 .The method of any one of embodiments 12-64, wherein the ASO comprises eight 2'-O- methylation modifications.

[0506] Embodiment 72.The method of any one of embodiments 12-64, wherein the ASO comprises nine 2'-O- methylation modifications.

[0507] Embodiment 73.The method of any one of embodiments 12-64, wherein the ASO comprises ten 2'-O- methylation modifications.

[0508] Embodiment 74.The method of any one of embodiments 12-64, wherein the ASO comprises eleven 2'-O- methylation modifications.

[0509] Embodiment 75.The method of any one of embodiments 12-64, wherein the ASO comprises twelve 2'-O- methylation modifications.

[0510] Embodiment 76.The method of any one of embodiments 12-75, wherein the ASO comprises the sequence of SEQ ID NOs: 45-144, or a variant thereof.

[0511] Embodiment 77.The method of embodiment 76, wherein the variant comprises about 1 , or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0512] Embodiment 78.The method of any one of embodiments 12-77, wherein the ASO has perfect sequence complementarity to an RNA molecule encoding POGK.

[0513] DBl / 161946556.2 102 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0514] Embodiment 79.The method of any one of embodiments 12-77, wherein the ASO has partial sequence complementarity to an RNA molecule encoding POGK.

[0515] Embodiment 8O.The method of embodiment 11 , wherein the nucleic acid is a splice suppressing oligonucleotide (SSO).

[0516] Embodiment 81 .The method of embodiment 80, wherein the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3 and / or POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof.

[0517] Embodiment 82.The method of any one of embodiments 80-81 , wherein the SSO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK to isoform 2.

[0518] Embodiment 83.The method of any one of embodiments 80-82, wherein the SSO is about 15 to about 16 nucleotides in length.

[0519] Embodiment 84.The method of any one of embodiments 80-83, wherein the SSO is about 15 nucleotides in length.

[0520] Embodiment 85.The method of any one of embodiments 80-84, wherein the SSO is about 16 nucleotides in length.

[0521] Embodiment 86.The method of any one of embodiments 80-85, wherein the SSO comprises at least one terminal 2’-O-methylation modification.

[0522] Embodiment 87.The method of any one of embodiments 80-86, wherein the SSO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O-methylation modifications are at a terminal location.

[0523] Embodiment 88.The method of any one of embodiments 80-87, wherein the SSO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.

[0524] Embodiment 89.The method of any one of embodiments 80-88, wherein the SSO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.

[0525] Embodiment 9O.The method of any one of embodiments 80-89, wherein the plurality of 2'-O-methylation modifications is at least 7 residues.

[0526] Embodiment 91 .The method of any one of embodiments 80-90, wherein the plurality of 2 -O-methylation modifications is at least 8 residues.

[0527] DBl / 161946556.2 103 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0528] Embodiment 92.The method of any one of embodiments 80-91 , wherein the plurality of 2'-O-methylation modifications is at least 9 residues.

[0529] Embodiment 93.The method of any one of embodiments 80-92, wherein the plurality of 2'-O-methylation modifications is at least 10 residues.

[0530] Embodiment 94.The method of any one of embodiments 80-93, wherein the plurality of 2'-O-methylation modifications is at least 11 residues.

[0531] Embodiment 95.The method of any one of embodiments 80-94, wherein the plurality of 2'-O-methylation modifications is at least 12 residues.

[0532] Embodiment 96.The method of any one of embodiments 80-95, wherein the plurality of 2 -O-methylation modifications is at least 13 residues.

[0533] Embodiment 97.The method of any one of embodiments 80-96, wherein the plurality of 2'-O-methylation modifications is at least 14 residues.

[0534] Embodiment 98.The method of any one of embodiments 80-97, wherein the plurality of 2'-O-methylation modifications is at least 15 residues.

[0535] Embodiment 99.The method of any one of embodiments 80-98, wherein the plurality of 2'-O-methylation modifications is at least 16 residues.

[0536] Embodiment 100. The method of any one of embodiments 80-99, wherein the plurality of 2'-O- methylation modifications is at least 6-16 residues.

[0537] Embodiment 101. The method of any one of embodiments 80-100, wherein the plurality of 2'-O- methylation modifications is at least 8-15 residues.

[0538] Embodiment 102. The method of any one of embodiments 80-101 , wherein the plurality of 2'-O- methylation modifications is at least 10-14 residues.

[0539] Embodiment 103. The method of any one of embodiments 80-102, wherein the plurality of 2'-O- methylation modifications is at least 11-13 residues.

[0540] Embodiment 104. The method of any one of embodiments 80-103, wherein the SSO comprises two 2'-O-methylation modifications.

[0541] DBl / 161946556.2 104 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0542] Embodiment 105. The method of any one of embodiments 80-104, wherein the SSO comprises three 2'-O-methylation modifications.

[0543] Embodiment 106. The method of any one of embodiments 80-105, wherein the SSO comprises four 2'-O-methylation modifications.

[0544] Embodiment 107. The method of any one of embodiments 80-106, wherein the SSO comprises five 2'-O-methylation modifications.

[0545] Embodiment 108. The method of any one of embodiments 80-107, wherein the SSO comprises six 2'-O-methylation modifications.

[0546] Embodiment 109. The method of any one of embodiments 80-108, wherein the SSO comprises seven 2'-O-methylation modifications.

[0547] Embodiment 110. The method of any one of embodiments 80-109, wherein the SSO comprises eight 2'-O-methylation modifications.

[0548] Embodiment 111. The method of any one of embodiments 80-110, wherein the SSO comprises nine 2'-O-methylation modifications.

[0549] Embodiment 112. The method of any one of embodiments 80-111 , wherein the SSO comprises ten 2'-O-methylation modifications.

[0550] Embodiment 113. The method of any one of embodiments 80-112, wherein the SSO comprises eleven 2'-O-methylation modifications.

[0551] Embodiment 114. The method of any one of embodiments 80-113, wherein the SSO comprises twelve 2'-O-methylation modifications.

[0552] Embodiment 115. The method of any one of embodiments 80-114, wherein the SSO comprises thirteen 2'-O-methylation modifications.

[0553] Embodiment 116. The method of any one of embodiments 80-115, wherein the SSO comprises fourteen 2'-O-methylation modifications.

[0554] Embodiment 117. The method of any one of embodiments 80-116, wherein the SSO comprises fifteen 2'-O-methylation modifications.

[0555] DBl / 161946556.2 105 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0556] Embodiment 118. The method of any one of embodiments 80-117, wherein the SSO comprises sixteen 2'-O-methylation modifications.

[0557] Embodiment 119. The method of any one of embodiments 80-118, wherein the SSO comprises at least one locked nucleic acid (LNA).

[0558] Embodiment 120. The method of any one of embodiments 80-119, wherein the SSO comprises two LNAs.

[0559] Embodiment 121. The method of any one of embodiments 80-120, wherein the SSO comprises three LNAs.

[0560] Embodiment 122. The method of any one of embodiments 80-121 , wherein the SSO comprises four LNAs.

[0561] Embodiment 123. The method of any one of embodiments 80-122, wherein the SSO comprises five LNAs.

[0562] Embodiment 124. The method of any one of embodiments 80-123, wherein the SSO comprises six

[0563] LNAs.

[0564] Embodiment 125. The method of any one of embodiments 80-124, wherein the SSO comprises seven LNAs.

[0565] Embodiment 126. The method of any one of embodiments 80-125, wherein the SSO comprises eight

[0566] LNAs.

[0567] Embodiment 127. The method of any one of embodiments 80-126, wherein the SSO comprises nine

[0568] LNAs.

[0569] Embodiment 128. The method of any one of embodiments 80-127, wherein the SSO comprises ten

[0570] LNAs.

[0571] Embodiment 129. The method of any one of embodiments 80-128, wherein the SSO comprises alternating 2'-O-methylation modifications and LNAs.

[0572] Embodiment 130. The method of any one of embodiments 80-129, wherein the SSO comprises the sequence of SEQ ID NOs: 145-244, or a variant thereof.

[0573] DBl / 161946556.2 106 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0574] Embodiment 131. The method of embodiment 130, wherein the variant comprises about 1, or about

[0575] 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0576] Embodiment 132. The method of any one of embodiments 80-131 , wherein the SSO has perfect sequence complementarity to an RNA molecule encoding POGK.

[0577] Embodiment 133. The method of any one of embodiments 80-131 , wherein the SSO has partial sequence complementarity to an RNA molecule encoding POGK.

[0578] Embodiment 134. A method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 1, wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 2, optionally wherein the pharmaceutical composition is selected from any one of embodiments 1 to 133, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 2, wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 1 , or optionally wherein the nucleic acid promotes the degradation of mRNA encoding POGK isoform 1 , and administering the cell to the subject.

[0579] Embodiment 135. The method of embodiment 134, wherein the nucleic acid is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA (ASO), and a guide RNA (gRNA).

[0580] Embodiment 136. The method of embodiment 134 or embodiment 135, wherein the nucleic acid has a sequence that complementary to and / or identical to at least 10, or at least 12, or at least 14, or at least 16 contiguous nucleotides of an mRNA encoding POGK isoform 2.

[0581] Embodiment 137. The method of any one of embodiments 134 to 136, wherein the nucleic acid has a sequence that complementary to and / or identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 .

[0582] Embodiment 138. The method of any one of embodiments 1 to 137, wherein the nucleic acid comprises a sugar modification, backbone modification, and / or a base modification.

[0583] Embodiment 139. The method of embodiment 138, wherein the backbone modification is a phosphorothioate modification.

[0584] DBl / 161946556.2 107 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0585] Embodiment 140. The method of embodiment 138 or embodiment 139, wherein the sugar modification comprises a 2'-O-methyl (2’OMe) and / or 2’-deoxy 2’-fluoro modification.

[0586] Embodiment 141. The method of any one of embodiments 138 to 140, wherein the base modification comprises pseudouridine, 5’-methylcytidine, N6-methyladenosine, inosine, and / or N7-methylguanosine.

[0587] Embodiment 142. A method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an inhibitor of pogo transposable element derived with KRAB domain (POGK) and / or TRIM28, optionally wherein the pharmaceutical composition is selected from any one of embodiments 1 to 141 , or (ii) contacting a cell with a pharmaceutical composition comprising an inhibitor of pogo transposable element derived with KRAB domain (POGK) and / or TRIM28 and administering the cell to the subject.

[0588] Embodiment 143. The method of embodiment 142, wherein the inhibitor is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like inhibitor, an antibody, an antibody-like molecule, a peptide, and a peptidomimetic.

[0589] Embodiment 144. The method of embodiment 142 or embodiment 143, wherein the inhibitor reduces the amount or activity of POGK and / or TRIM28.

[0590] Embodiment 145. The method of any one of embodiments 142 to 144, wherein the inhibitor reduces the amount or activity of at least one ribosomal protein gene.

[0591] Embodiment 146. The method of embodiment 145, wherein the ribosomal protein is selected from RPLP1 , RPL11 , RPL13, RPL15, RPL36, RPS16, RPS28, and RPS29.

[0592] Embodiment 147. The method of any one of embodiments 142 to 146, wherein the inhibitor inhibits the transcription of one or more of RPL13, RPL15, RPS16, RPS28, and RPS29.

[0593] Embodiment 148. The method of any one of embodiments 1 to 147, wherein the cancer is selected from breast cancer, bone cancer, abdominal cancer, adrenal cancer, bladder cancer, blood cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, intestinal cancer, kidney cancer, leukemia, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma cancer, skin cancer, spleen cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulval cancer.

[0594] DBl / 161946556.2 108 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0595] Embodiment 149. The method of any one of embodiments 1 to 148, wherein the cancer is selected from acute myeloid leukemia, adrenocortical carcinoma, bladder urothelial carcinoma, breast ductal carcinoma, breast lobular carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, esophageal carcinoma, gastric adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, lower grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, paraganglioma & pheochromocytoma, prostate adenocarcinoma, sarcoma, skin cutaneous melanoma, testicular germ cell cancer, thymoma, thyroid papillary carcinoma, uterine carcinosarcoma, uterine corpus endometrioid carcinoma, and uveal melanoma.

[0596] Embodiment 150. The method of any one of embodiments 1 to 149, wherein the cancer is selected from breast cancer, pancreatic adenocarcinoma, liver cancer (e.g. , hepatocellular carcinoma), lung cancer (e.g., lung adenocarcinoma and lung squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), ovarian cancer (e.g., ovarian serous cystadenocarcinoma).

[0597] Embodiment 151. The method of any one of embodiments 1 to 150, wherein the cancer is triplenegative breast cancer (TNBC).

[0598] Embodiment 152. The method of any one of embodiments 1 to 151 , wherein the method further comprises the step of administering to the subject a second pharmaceutical composition comprising an anti-immune checkpoint agent.

[0599] Embodiment 153. The method of embodiment 152, wherein the second pharmaceutical composition is administered before administering the pharmaceutical composition.

[0600] Embodiment 154. The method of embodiment 152, wherein the pharmaceutical composition is administered before administering the second pharmaceutical composition.

[0601] Embodiment 155. The method of embodiment 152, wherein the pharmaceutical composition and the second pharmaceutical composition are contemporaneously administered.

[0602] Embodiment 156. The method of any one of embodiments 152 to 155, wherein the anti-immune checkpoint agent is or comprises an antibody that is capable of binding an immune checkpoint molecule.

[0603] DBl / 161946556.2 109 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0604] Embodiment 157. The method of embodiment 156, wherein the antibody is capable of binding programmed cell death protein 1 (PD 1), a PD 1 ligand, and / or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).

[0605] Embodiment 158. The method of embodiment 156, wherein the antibody is capable of binding PD-1 and is optionally selected from pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), cemiplimab (LIBTAYO), pidilizumab (CT 011), dostarlimab (JEMPERLI), Spartalizumab (PDR001), RMP1-14, balstilimab (AGEN2034), Vopratelimab (JTX-4014), Camrelizumab (SHR1210), Sintilimab (IBI308), Tislelizumab (BGB-A317), Toripalimab (JS 001), INCMGA00012 (MGA012), AMP-224, and AMP-514.

[0606] Embodiment 159. The method of embodiment 156, wherein the antibody is capable of binding PD-L1 and is optionally selected from atezolizumab (TECENTRIQ), avelumab (BAVENCIO), durvalumab (IMFINZI), KN035, a lymphocyte activation gene-3 (LAG-3, CD223) inhibitor, relatlimab (BMS-986,016), relatlimab (BMS-986,016) in combination with opdualag (nivolumab) (nivolumab and relatlimab-rmbw), and Cosibelimab (CK-301).

[0607] Embodiment 160. The method of embodiment 156, wherein the antibody is capable of binding CTLA- 4 and is optionally Ipilimumab (YERVOY) or Tremelimumab (IMJUDO).

[0608] Embodiment 161. The method of any one of embodiments 1 to 160, wherein the method further comprises selecting a subject for the treatment.

[0609] Embodiment 162. The method of embodiment 161, wherein the subject is selected for the treatment based on a reduced expression or activity of POGK in a tumor sample compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0610] Embodiment 163. The method of embodiment 162, wherein the expression or activity of POGK is assayed by evaluating the presence, absence, or level of expression or activity of POGK protein or an mRNA encoding POGK.

[0611] Embodiment 164. A method of determining a cancer treatment for a patient, the method comprising:

[0612] (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and

[0613] DBl / 161946556.2 110 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0614] (b) determining a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0615] Embodiment 165. A method for selecting a subject for a cancer treatment, the method comprising:

[0616] (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and

[0617] (b) selecting the subject for a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0618] Embodiment 166. A method of treating cancer, the method comprising:

[0619] (a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and

[0620] (b) administering to the subject for a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

[0621] Embodiment 167. The method of any one of embodiments 164 to 166, wherein the biological sample is obtained from blood, serum, saliva, plasma, a tissue sample, a fresh tissue sample, frozen tumor tissue specimen, cultured cells, circulating tumor cells, or a formalin-fixed paraffin-embedded tumor tissue specimen.

[0622] Embodiment 168. The method of any one of embodiments 164 to 167, wherein the biological sample is a biopsy sample selected from endoscopic biopsy, bone marrow biopsy, endoscopic biopsy (e.g., cystoscopy, bronchoscopy and colonoscopy), needle biopsy (e.g., fine-needle aspiration, core needle

[0623] DBl / 161946556.2 111 Attorney Docket No.: BID-014PC / 110304-5014-PC biopsy, vacuum-assisted biopsy, X-ray-assisted biopsy, computerized tomography (CT)-assisted biopsy, magnetic resonance imaging (MRI)-assisted biopsy and ultrasound-assisted biopsy), skin biopsy (e.g., shave biopsy, punch biopsy, and incisional biopsy) and surgical biopsy.

[0624] Embodiment 169. The method of any one of embodiments 164 to 168, wherein the biological sample comprises a body fluid selected from blood, plasma, serum, lacrimal fluid, tears, bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy sample, cell-containing body fluid, free floating nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swab, vaginal swab, oral swab, nasal swab, washing or lavage such as a ductal lavage or broncheoalveolar lavage, aspirate, scraping, bone marrow specimen, tissue biopsy specimen, surgical specimen, feces, other body fluids, secretions, and / or excretions, and / or cells therefrom.

[0625] Embodiment 170. The method of any one of embodiments 164 to 169, wherein the evaluating is performed by DNA sequencing, RNA sequencing, immunohistochemical staining, western blotting, in cell western, immunofluorescent staining, ELISA, and fluorescent activating cell sorting (FACS) or a combination thereof.

[0626] Embodiment 171. The method of any one of embodiments 164 to 170, wherein the evaluating is performed by contacting the sample with an agent that specifically binds to POGK protein and / or TRIM28 protein.

[0627] Embodiment 172. The method of embodiment 171, wherein the agent that specifically binds to POGK protein and / or TRIM28 protein is an antibody or fragment thereof, optionally wherein the antibody is a recombinant antibody, a monoclonal antibody, a polyclonal antibody, or fragment thereof.

[0628] Embodiment 173. The method of any one of embodiments 164 to 172, wherein the evaluating is performed by contacting the sample with an agent that specifically binds to a nucleic acid encoding POGK protein and / or TRIM28 protein.

[0629] Embodiment 174. The method of embodiment 173, wherein the nucleic acid is mRNA or cDNA.

[0630] Embodiment 175. The method of embodiment 173 or embodiment 174, wherein the agent that specifically binds to one or more of the nucleic acids is a nucleic acid primer or probe.

[0631] Embodiment 176. The method of any one of embodiments 164 to 175, wherein the POGK therapy is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like

[0632] DBl / 161946556.2 112 Attorney Docket No.: BID-014PC / 110304-5014-PC inhibitor, an antibody, an antibody-like molecule, a peptide, a peptidomimetic, and a nucleic encoding POGK isoform 1.

[0633] Embodiment 177. The method embodiment 176, wherein the POGK therapy is or comprises a nucleic acid encoding POGK isoform 1.

[0634] Embodiment 178. The method of embodiment 177, wherein the nucleic acid is DNA.

[0635] Embodiment 179. The method of embodiment 177 or embodiment 167, wherein the nucleic acid is an expression vector.

[0636] Embodiment 180. The method of embodiment 179, wherein the expression vector is a viral vector.

[0637] Embodiment 181. The method of embodiment 180, wherein the viral vector is selected from a lentivirus vector (LV) a retrovirus vector (RV), an adenovirus vector (AV), an adeno-associated virus vector (AAV), and an a virus vector (e.g., a Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV) vector).

[0638] Embodiment 182. The method of embodiment 176 or embodiment 177, wherein the nucleic acid is mRNA.

[0639] Embodiment 183. The method of embodiment 182, wherein the nucleic acid is a modified mRNA

[0640] (mmRNA).

[0641] Embodiment 184. The method of embodiment 183, wherein the mmRNA comprises at least one modified nucleotide selected from pseudouridine C+1), N1 -methyl-pseudouridine, N6-methyladenosine (m6A), N1 -methyladenosine (m1A), 5-methylcytosine (m5C), and 5-hydroxymethylcytosine (hm5C).

[0642] Embodiment 185. The method of embodiment 183 or embodiment 184, wherein the mmRNA further comprises a 5’ untranslated region (5’-UTR), and a 3’ untranslated region (3’-UTR).

[0643] Embodiment 186. The method of embodiment 183 or embodiment 184, wherein the mmRNA further comprises a 5' cap structure and / or a 3’-poly(A) tail.

[0644] Embodiment 187. The method of any one of embodiments 164 to 177, wherein the POGK therapy is or comprises an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA.

[0645] Embodiment 188. The method of embodiment 187, wherein the nucleic acid is an antisense oligonucleotide (ASO).

[0646] DBl / 161946556.2 113 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0647] Embodiment 189. The method of embodiment 188, wherein the ASO inhibits the formation of mRNA encoding POGK isoform 2, and / or the ASO inhibits the formation of mRNA encoding POGK isoform 1 , and / or promotes the formation of mRNA encoding POGK isoform 1 .

[0648] Embodiment 190. The method of embodiment 188 or embodiment 189, wherein the ASO promotes the inclusion of exon 2 of POGK in the mRNA, optionally wherein the ASO promotes the formation of an mRNA comprising exons 2, 3, 4, 5, and 6.

[0649] Embodiment 191. The method of any one of embodiments 188 to 180, wherein the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long.

[0650] Embodiment 192. The method of any one of embodiments 164 to 191 , wherein the POGK therapy is or comprises an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 2, wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 1 , or optionally wherein the nucleic acid promotes the degradation of mRNA encoding POGK isoform 1.

[0651] Embodiment 193. The method of embodiment 192, wherein the nucleic acid is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA (ASO), and a guide RNA (gRNA).

[0652] Embodiment 194. The method of embodiment 192 or embodiment 193, wherein the nucleic acid has a sequence that complementary to and / or identical to at least 10, or at least 12, or at least 14, or at least 16 contiguous nucleotides of an mRNA encoding POGK isoform 2.

[0653] Embodiment 195. The method of any one of embodiments 164 to 194, wherein the nucleic acid has a sequence that complementary to and / or identical to less that about 16, or less that about 14, or less that about 12, or less that about 10 contiguous nucleotides of an mRNA encoding POGK isoform 1 .

[0654] Embodiment 196. The method of any one of embodiments 164 to 195, wherein the nucleic acid comprises a sugar modification, backbone modification, and / or a base modification.

[0655] Embodiment 197. The method of embodiment 196, wherein the backbone modification is a phosphorothioate modification.

[0656] Embodiment 198. The method of embodiment 195 or embodiment 196, wherein the sugar modification comprises a 2'-O-methyl (2’OMe) and / or 2’-deoxy 2’-fluoro modification.

[0657] DBl / 161946556.2 114 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0658] Embodiment 199. The method of any one of embodiments 195 to 198, wherein the base modification comprises pseudouridine, 5’-methylcytidine, N6-methyladenosine, inosine, and / or N7-methylguanosine.

[0659] Embodiment 200. The method of any one of embodiments 164 to 199, wherein the POGK therapy is or comprises an inhibitor of pogo transposable element derived with KRAB domain (POGK) and / or TRIM28.

[0660] Embodiment 201 . The method of embodiment 200, wherein the inhibitor is selected from a small interference RNA (siRNA), a short hairpin RNA (shRNA), a CRISPR RNA (crRNA), a microRNA (miRNA), an antisense RNA, a guide RNA (gRNA), a small molecule, a proteolysis targeting chimera (PROTAC)-like inhibitor, an antibody, an antibody-like molecule, a peptide, and a peptidomimetic.

[0661] Embodiment 202. The method of embodiment 200 or embodiment 201 , wherein the inhibitor reduces the amount or activity of POGK and / or TRIM28.

[0662] Embodiment 203. The method of any one of embodiments 200 to 202, wherein the inhibitor reduces the amount or activity of at least one ribosomal protein gene.

[0663] Embodiment 204. The method of embodiment 203, wherein the ribosomal protein is selected from RPLP1 , RPL11 , RPL13, RPL15, RPL36, RPS16, RPS28, and RPS29.

[0664] Embodiment 205. The method of any one of embodiments 200 to 204, wherein the inhibitor inhibits the transcription of one or more of RPL13, RPL15, RPS16, RPS28, and RPS29.

[0665] Embodiment 206. The method of any one of embodiments 1 to 205, wherein the cancer is metastatic.

[0666] Embodiment 207. The method of embodiment 206, wherein the tumor has metastasized to a tissue or an organ.

[0667] Embodiment 208. The method of any one of embodiments 1 to 207, wherein the subject is a mammal.

[0668] Embodiment 209. The method of embodiment 208, wherein the mammal is a human.

[0669] Embodiment 210. A kit comprising the pharmaceutical composition of any one of embodiments 1-209 with instructions for use in modulating and / or modifying and / or delivering the isolated nucleic acid.

[0670] DBl / 161946556.2 115 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0671] Embodiment 211. A composition comprising an antisense oligonucleotide, wherein the composition attenuates, weakens, reduces, decreases, or ablates the splicing that results in isoform 2 of POGK, wherein: the antisense oligonucleotide comprises at least one 2'-O-methylation modifications and at least six internal phosphorothioate deoxyribonucleotides; and the antisense oligonucleotide is about 15 to about 20 nucleotides in length.

[0672] Embodiment 212. The composition of embodiment 211 , wherein the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of isoform 1 of POGK, optionally inhibiting splicing of isoform 1 of POGK, to isoform 2 of POGK.

[0673] Embodiment 213. The composition of any one of embodiments 211 -212, wherein the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK, optionally splicing of POGK, to isoform 2.

[0674] Embodiment 214. The composition of any one of embodiments 211 -213, wherein the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long.

[0675] Embodiment 215. The composition of any one of embodiments 211 -214, wherein the ASO is about 15 to about 20 nucleotides in length.

[0676] Embodiment 216. The composition of any one of embodiments 211 -215, wherein the ASO is about

[0677] 15 nucleotides in length.

[0678] Embodiment 217. The composition of any one of embodiments 211 -216, wherein the ASO is about

[0679] 16 nucleotides in length.

[0680] Embodiment 218. The composition of any one of embodiments 211 -217, wherein the ASO is about

[0681] 17 nucleotides in length.

[0682] Embodiment 219. The composition of any one of embodiments 211 -218, wherein the ASO is about

[0683] 18 nucleotides in length.

[0684] Embodiment 220. The composition of any one of embodiments 211 -219, wherein the ASO is about

[0685] 19 nucleotides in length.

[0686] Embodiment 221. The composition of any one of embodiments 211 -220, wherein the ASO is about

[0687] 20 nucleotides in length.

[0688] DBl / 161946556.2 116 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0689] Embodiment 222. The composition of any one of embodiments 211 -221 , wherein the ASO comprises at least one internal phosphorothioate deoxyribonucleotide.

[0690] Embodiment 223. The composition of any one of embodiments 211 -222, wherein the ASO comprises at least two internal phosphorothioate deoxyribonucleotides.

[0691] Embodiment 224. The composition of any one of embodiments 211 -223, wherein the ASO comprises at least three internal phosphorothioate deoxyribonucleotides.

[0692] Embodiment 225. The composition of any one of embodiments 211 -224, wherein the ASO comprises at least four internal phosphorothioate deoxyribonucleotides.

[0693] Embodiment 226. The composition of any one of embodiments 211 -225, wherein the ASO comprises at least five internal phosphorothioate deoxyribonucleotides.

[0694] Embodiment 227. The composition of any one of embodiments 211 -226, wherein the ASO comprises at least six internal phosphorothioate deoxyribonucleotides.

[0695] Embodiment 228. The composition of any one of embodiments 211 -227, wherein the ASO comprises at least seven internal phosphorothioate deoxyribonucleotides.

[0696] Embodiment 229. The composition of any one of embodiments 211 -228, wherein the ASO comprises at least eight internal phosphorothioate deoxyribonucleotides.

[0697] Embodiment 230. The composition of any one of embodiments 211 -229, wherein the ASO comprises at least nine internal phosphorothioate deoxyribonucleotides.

[0698] Embodiment 231 . The composition of any one of embodiments 211 -230, wherein the ASO comprises at least ten internal phosphorothioate deoxyribonucleotides.

[0699] Embodiment 232. The composition of any one of embodiments 211 -231 , wherein the ASO comprises at least eleven internal phosphorothioate deoxyribonucleotides.

[0700] Embodiment 233. The composition of any one of embodiments 211 -232, wherein the ASO comprises at least twelve internal phosphorothioate deoxyribonucleotides.

[0701] Embodiment 234. The composition of any one of embodiments 211 -233, wherein the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides.

[0702] DBl / 161946556.2 117 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0703] Embodiment 235. The composition of any one of embodiments 211 -234, wherein the ASO comprises at least 6-12 internal phosphorothioate deoxyribonucleotides.

[0704] Embodiment 236. The composition of any one of embodiments 211 -235, wherein the ASO comprises at least 8-10 internal phosphorothioate deoxyribonucleotides.

[0705] Embodiment 237. The composition of any one of embodiments 211 -236, wherein the ASO comprises

[0706] 8 internal phosphorothioate deoxyribonucleotides.

[0707] Embodiment 238. The composition of any one of embodiments 211 -237, wherein the ASO comprises

[0708] 9 internal phosphorothioate deoxyribonucleotides.

[0709] Embodiment 239. The composition of any one of embodiments 211 -238, wherein the ASO comprises

[0710] 10 internal phosphorothioate deoxyribonucleotides.

[0711] Embodiment 240. The composition of any one of embodiments 211 -239, wherein the ASO comprises at least one terminal 2’-O-methylation modification.

[0712] Embodiment 241 . The composition of any one of embodiments 211 -240, wherein the ASO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O-methylation modifications are at a terminal location.

[0713] Embodiment 242. The composition of any one of embodiments 211 -241 , wherein the ASO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1, or 2, or 3, or 4, or 5.

[0714] Embodiment 243. The composition of any one of embodiments 211 -242, wherein the ASO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1, or 2, or 3, or 4, or 5.

[0715] Embodiment 244. The composition of any one of embodiments 211 -243, wherein the plurality of 2'- O-methyl ation modifications is at least 7 residues.

[0716] Embodiment 245. The composition of any one of embodiments 211 -244, wherein the plurality of 2'- O-methylation modifications is at least 8 residues.

[0717] Embodiment 246. The composition of any one of embodiments 211 -245, wherein the plurality of 2'- O-methyl ation modifications is at least 9 residues.

[0718] Embodiment 247. The composition of any one of embodiments 211 -246, wherein the plurality of 2'- O-methylation modifications is at least 10 residues.

[0719] DBl / 161946556.2 118 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0720] Embodiment 248. The composition of any one of embodiments 211 -247, wherein the plurality of 2'- O-methylation modifications is at least 11 residues.

[0721] Embodiment 249. The composition of any one of embodiments 211 -248, wherein the plurality of 2'- O-methylation modifications is at least 12 residues.

[0722] Embodiment 250. The composition of any one of embodiments 211 -249, wherein the plurality of 2'- O-methylation modifications is at least 13 residues.

[0723] Embodiment 251 . The composition of any one of embodiments 211 -250, wherein the plurality of 2'- O-methylation modifications is at least 14 residues.

[0724] Embodiment 252. The composition of any one of embodiments 211 -251 , wherein the plurality of 2'- O-methylation modifications is at least 15 residues.

[0725] Embodiment 253. The composition of any one of embodiments 211 -252, wherein the plurality of 2'- O-methylation modifications is at least 16 residues.

[0726] Embodiment 254. The composition of any one of embodiments 211 -253, wherein the plurality of 2'- O-methylation modifications is at least 17 residues.

[0727] Embodiment 255. The composition of any one of embodiments 211 -254, wherein the plurality of 2'- O-methylation modifications is at least 18 residues.

[0728] Embodiment 256. The composition of any one of embodiments 211 -255, wherein the plurality of 2'- O-methylation modifications is at least 19 residues.

[0729] Embodiment 257. The composition of any one of embodiments 211 -256, wherein the plurality of 2'- O-methylation modifications is at least 6-20 residues.

[0730] Embodiment 258. The composition of any one of embodiments 211 -257, wherein the plurality of 2'- O-methylation modifications is at least 9-15 residues.

[0731] Embodiment 259. The composition of any one of embodiments 211 -258, wherein the plurality of 2'- O-methylation modifications is at least 10-14 residues.

[0732] Embodiment 260. The composition of any one of embodiments 211 -259, wherein the plurality of 2'- O-methylation modifications is at least 11-13 residues.

[0733] DBl / 161946556.2 119 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0734] Embodiment 261 . The composition of any one of embodiments 211 -260, wherein the ASO comprises two 2'-0-methylation modifications.

[0735] Embodiment 262. The composition of any one of embodiments 211 -261 , wherein the ASO comprises three 2'-O-methylation modifications.

[0736] Embodiment 263. The composition of any one of embodiments 211 -262, wherein the ASO comprises four 2'-O-methylation modifications.

[0737] Embodiment 264. The composition of any one of embodiments 211 -263, wherein the ASO comprises five 2'-O-methylation modifications.

[0738] Embodiment 265. The composition of any one of embodiments 211 -264, wherein the ASO comprises six 2'-O-methylation modifications.

[0739] Embodiment 266. The composition of any one of embodiments 211 -265, wherein the ASO comprises seven 2'-O-methylation modifications.

[0740] Embodiment 267. The composition of any one of embodiments 211 -266, wherein the ASO comprises eight 2'-O-methylation modifications.

[0741] Embodiment 268. The composition of any one of embodiments 211 -267, wherein the ASO comprises nine 2'-O-methylation modifications.

[0742] Embodiment 269. The composition of any one of embodiments 211 -268, wherein the ASO comprises ten 2'-O-methylation modifications.

[0743] Embodiment 270. The composition of any one of embodiments 211 -269, wherein the ASO comprises eleven 2'-O-methylation modifications.

[0744] Embodiment 271 . The composition of any one of embodiments 211 -270, wherein the ASO comprises twelve 2'-O-methylation modifications.

[0745] Embodiment 272. The composition of any one of embodiments 211 -271 , wherein the ASO comprises the sequence of SEQ ID NOs: 45-144, or a variant thereof.

[0746] Embodiment 273. The composition of embodiment 272, wherein the variant comprises about 1 , or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0747] DBl / 161946556.2 120 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0748] Embodiment 274. The composition of any one of embodiments 211 -273, wherein the ASO has perfect sequence complementarity to an RNA molecule encoding POGK.

[0749] Embodiment 275. The composition of any one of embodiments 211 -274, wherein the ASO has partial sequence complementarity to an RNA molecule encoding POGK.

[0750] Embodiment 276. A composition comprising an splice suppressing oligonucleotide, wherein the composition targets or suppresses the POGK gene or an isoform thereof, wherein: the splice suppressing oligonucleotide comprises at least one 2'-O-methylation modifications; and the splice suppressing oligonucleotide is about 15 to about 16 nucleotides in length.

[0751] Embodiment 277. The composition of embodiment 276, wherein the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3 and / or POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof.

[0752] Embodiment 278. The composition of any one of embodiments 276-277, wherein the SSO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK to isoform 2.

[0753] Embodiment 279. The composition of any one of embodiments 276-278, wherein the SSO is about 15 to about 16 nucleotides in length.

[0754] Embodiment 280. The composition of any one of embodiments 276-279, wherein the SSO is about

[0755] 15 nucleotides in length.

[0756] Embodiment 281 . The composition of any one of embodiments 276-280, wherein the SSO is about

[0757] 16 nucleotides in length.

[0758] Embodiment 282. The composition of any one of embodiments 276-281 , wherein the SSO comprises at least one terminal 2’-O-methylation modification.

[0759] Embodiment 283. The composition of any one of embodiments 276-282, wherein the SSO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O-methylation modifications are at a terminal location.

[0760] Embodiment 284. The composition of any one of embodiments 276-283, wherein the SSO comprises at least a 3’ terminal 2'-O-methylation modification, optionally 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.

[0761] DBl / 161946556.2 121 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0762] Embodiment 285. The composition of any one of embodiments 276-284, wherein the SSO comprises at least a 5’ terminal 2'-O-methylation modification, optionally 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.

[0763] Embodiment 286. The composition of any one of embodiments 276-285, wherein the plurality of 2'- O-methylation modifications is at least 7 residues.

[0764] Embodiment 287. The composition of any one of embodiments 276-286, wherein the plurality of 2'- O-methylation modifications is at least 8 residues.

[0765] Embodiment 288. The composition of any one of embodiments 276-287, wherein the plurality of 2'- O-methylation modifications is at least 9 residues.

[0766] Embodiment 289. The composition of any one of embodiments 276-288, wherein the plurality of 2'- O-methylation modifications is at least 10 residues.

[0767] Embodiment 290. The composition of any one of embodiments 276-289, wherein the plurality of 2'- O-methylation modifications is at least 11 residues.

[0768] Embodiment 291 . The composition of any one of embodiments 276-290, wherein the plurality of 2'- O-methylation modifications is at least 12 residues.

[0769] Embodiment 292. The composition of any one of embodiments 276-291 , wherein the plurality of 2'- O-methylation modifications is at least 13 residues.

[0770] Embodiment 293. The composition of any one of embodiments 276-292, wherein the plurality of 2'- O-methylation modifications is at least 14 residues.

[0771] Embodiment 294. The composition of any one of embodiments 276-293, wherein the plurality of 2'- O-methylation modifications is at least 15 residues.

[0772] Embodiment 295. The composition of any one of embodiments 276-294, wherein the plurality of 2'- O-methylation modifications is at least 16 residues.

[0773] Embodiment 296. The composition of any one of embodiments 276-295, wherein the plurality of 2'- O-methylation modifications is at least 6-16 residues.

[0774] Embodiment 297. The composition of any one of embodiments 276-296, wherein the plurality of 2'- O-methylation modifications is at least 8-15 residues.

[0775] DBl / 161946556.2 122 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0776] Embodiment 298. The composition of any one of embodiments 276-297, wherein the plurality of 2'- O-methylation modifications is at least 10-14 residues.

[0777] Embodiment 299. The composition of any one of embodiments 276-298, wherein the plurality of 2'- O-methylation modifications is at least 11-13 residues.

[0778] Embodiment 300. The composition of any one of embodiments 276-299, wherein the SSO comprises two 2'-O-methylation modifications.

[0779] Embodiment 301 . The composition of any one of embodiments 276-300, wherein the SSO comprises three 2'-O-methylation modifications.

[0780] Embodiment 302. The composition of any one of embodiments 276-301 , wherein the SSO comprises four 2'-O-methylation modifications.

[0781] Embodiment 303. The composition of any one of embodiments 276-302, wherein the SSO comprises five 2'-0-methylation modifications.

[0782] Embodiment 304. The composition of any one of embodiments 276-303, wherein the SSO comprises six 2'-O-methylation modifications.

[0783] Embodiment 305. The composition of any one of embodiments 276-304, wherein the SSO comprises seven 2'-O-methylation modifications.

[0784] Embodiment 306. The composition of any one of embodiments 276-305, wherein the SSO comprises eight 2'-O-methylation modifications.

[0785] Embodiment 307. The composition of any one of embodiments 276-306, wherein the SSO comprises nine 2'-O-methylation modifications.

[0786] Embodiment 308. The composition of any one of embodiments 276-307, wherein the SSO comprises ten 2'-O-methylation modifications.

[0787] Embodiment 309. The composition of any one of embodiments 276-308, wherein the SSO comprises eleven 2'-O-methylation modifications.

[0788] Embodiment 310. The composition of any one of embodiments 276-309, wherein the SSO comprises twelve 2'-O-methylation modifications.

[0789] DBl / 161946556.2 123 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0790] Embodiment 311 . The composition of any one of embodiments 276-310, wherein the SSO comprises thirteen 2'-0-methylation modifications.

[0791] Embodiment 312. The composition of any one of embodiments 276-311 , wherein the SSO comprises fourteen 2'-O-methylation modifications.

[0792] Embodiment 313. The composition of any one of embodiments 276-312, wherein the SSO comprises fifteen 2'-O-methylation modifications.

[0793] Embodiment 314. The composition of any one of embodiments 276-313, wherein the SSO comprises sixteen 2'-O-methylation modifications.

[0794] Embodiment 315. The method of any one of embodiments 134-314, wherein the SSO comprises at least one locked nucleic acid (LNA).

[0795] Embodiment 316. The method of any one of embodiments 134-315, wherein the SSO comprises two

[0796] LNAs.

[0797] Embodiment 317. The method of any one of embodiments 134-316, wherein the SSO comprises three LNAs.

[0798] Embodiment 318. The method of any one of embodiments 134-317, wherein the SSO comprises four

[0799] LNAs.

[0800] Embodiment 319. The method of any one of embodiments 134-318, wherein the SSO comprises five

[0801] LNAs.

[0802] Embodiment 320. The method of any one of embodiments 134-319, wherein the SSO comprises six LNAs.

[0803] Embodiment 321 . The method of any one of embodiments 134-320, wherein the SSO comprises seven LNAs.

[0804] Embodiment 322. The method of any one of embodiments 134-321 , wherein the SSO comprises eight LNAs.

[0805] Embodiment 323. The method of any one of embodiments 134-322, wherein the SSO comprises nine LNAs.

[0806] DBl / 161946556.2 124 Attorney Docket No.: BID-014PC / 110304-5014-PC

[0807] Embodiment 324. The method of any one of embodiments 134-323, wherein the SSO comprises ten

[0808] LNAs.

[0809] Embodiment 325. The method of any one of embodiments 134-324, wherein the SSO comprises alternating 2'-O-methylation modifications and LNAs.

[0810] Embodiment 326. The composition of any one of embodiments 134-325, wherein the SSO comprises the sequence of SEQ ID NOs: 145-244, or a variant thereof.

[0811] Embodiment 327. The composition of embodiment 326, wherein the variant comprises about 1 , or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

[0812] Embodiment 328. The composition of any one of embodiments 134-327, wherein the SSO has perfect sequence complementarity to an RNA molecule encoding POGK.

[0813] Embodiment 329. The composition of any one of embodiments 134-327, wherein the SSO has partial sequence complementarity to an RNA molecule encoding POGK.

[0814] Embodiment 330. A method of treating cancer in a subject in need thereof, the method comprising: i) administering to the subject a pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises an isolated nucleic acid, small molecule, or protein inhibiting pogo transposable element derived with KRAB domain (POGK) isoform 1 or (ii) contacting a cell with a pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises an isolated nucleic acid, small molecule, or protein inhibitor of pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.

[0815] DBl / 161946556.2 125

Claims

1. Attorney Docket No.: BID-014PC / 110304-5014-PCCLAIMSWhat is claimed is:1 . A method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA and administering the cell to the subject.

2. The method of claim 2, wherein the nucleic acid is an antisense oligonucleotide (ASO).

3. The method of claim 2, wherein the ASO targets, binds, and / or modulates POGK at exon 5 and / or exon 6.

4. The method of any one of claims 2-3, wherein the ASO targets, binds, and / or modulates POGK at exon 5.

5. The method of any one of claims 2-3, wherein the ASO targets, binds, and / or modulates POGK at exon 6.

6. The method of claim 2, wherein the ASO inhibits the formation of mRNA encoding POGK isoform 2, and / or the ASO inhibits the formation of mRNA encoding POGK isoform 1 , and / or promotes the formation of mRNA encoding POGK isoform 1.

7. The method of any one of claims 2-6, wherein the ASO promotes the inclusion of exon 2 of POGK in the mRNA, optionally wherein the ASO promotes the formation of an mRNA comprising exons 2, 3, 4, 5, and 6.

8. The method of any one of claims 1 to 7, wherein the isolated nucleic acid targets the KRAB domain of POGK and suppresses POGK.

9. The method of any one of claims 3-8, wherein the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of isoform 1 of POGK, optionally inhibiting splicing of isoform 1 of POGK to isoform 2 of POGK.126DBl / 161946556.2Attorney Docket No.: BID-014PC / 110304-5014-PC10. The method of any one of claims 3-8, wherein the ASO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK, optionally splicing of POGK to isoform 2.11 . The method of any one of claims 3-10, wherein the ASO is about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50 nucleotides long.

12. The method of any one of claims 3-11 , wherein the ASO comprises at least one internal phosphorothioate deoxyribonucleotide.

13. The method of any one of claims 3-12, wherein the ASO comprises a plurality of 2'-O-methylation modifications, optionally wherein the plurality of 2'-O-methylation modifications are at a terminal location.

14. The method of any one of claims 3-13, wherein the ASO comprises the sequence of SEQ ID NOs: 45-144, or a variant thereof.

15. The method of any one of claims 3-14, wherein the ASO comprises the sequence of SEQ ID NOs: 45-69, or a variant thereof.

16. The method of claim 14 or 15, wherein the variant comprises about 1 , or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

17. The method of any one of claims 3-16, wherein the ASO has perfect sequence complementarity to an RNA molecule encoding POGK.

18. The method of any one of claims 3-16, wherein the ASO has partial sequence complementarity to an RNA molecule encoding POGK.

19. A method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that is a splice suppressing oligonucleotide (SSO) and is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA and administering the cell to the subject.DBl / 161946556.2 127Attorney Docket No.: BID-014PC / 110304-5014-PC20. The method of claim 19, wherein the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3 and / or POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof.

21. The method of claim 19, wherein the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 3, or suppresses the splicing of POGK, or an isoform thereof.

22. The method of claim 19, wherein the SSO targets, binds and / or modulates one or more splicing enhancers, splicing suppressors, regulatory sequences, or intronic regions flanking POGK exon 4, or suppresses the splicing of POGK, or an isoform thereof.

23. The method of any one of claims 19-22, wherein the SSO attenuates, weakens, reduces, decreases, or ablates the splicing of POGK to isoform 2.

24. The method of any one of claims 19-23, wherein the SSO is about 15 to about 16 nucleotides in length, optionally wherein the SSO comprises at least one terminal 2’-O-methylation modification.

25. The method of any one of claims 19-24, wherein the SSO comprises at least one locked nucleic acid (LNA).

26. The method of any one of claims 19-25, wherein the SSO comprises the sequence of SEQ ID NOs: 145-244, or a variant thereof.

27. The method of any one of claims 19-26, wherein the SSO comprises the sequence of SEQ ID NOs: 145-150, or a variant thereof.

28. The method of claim 26 or 27, wherein the variant comprises about 1 , or about 2, or about 3, or about 4, or about 5 mutations, the mutations selected from substitutions, deletions, and insertions.

29. The method of any one of claims 19-28, wherein the SSO has perfect sequence complementarity to an RNA molecule encoding POGK., optionally wherein the SSO has partial sequence complementarity to an RNA molecule encoding POGK.DBl / 161946556.2 128Attorney Docket No.: BID-014PC / 110304-5014-PC30. A method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 1 , wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 2, optionally wherein the pharmaceutical composition is selected from any one of claims 1 to 29, or (ii) contacting a cell with a pharmaceutical composition comprising an isolated nucleic acid that specifically promotes the degradation of mRNA encoding POGK isoform 2, wherein the nucleic acid does not substantially promote the degradation of mRNA encoding POGK isoform 1 , or optionally wherein the nucleic acid promotes the degradation of mRNA encoding POGK isoform 1 , and administering the cell to the subject.31 . A method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a pharmaceutical composition comprising an inhibitor of pogo transposable element derived with KRAB domain (POGK) and / or TRIM28, optionally wherein the pharmaceutical composition is selected from any one of claims 1 to 29, or (ii) contacting a cell with a pharmaceutical composition comprising an inhibitor of pogo transposable element derived with KRAB domain (POGK) and / or TRIM28 and administering the cell to the subject.

32. A method of determining a cancer treatment for a patient, the method comprising:(a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and(b) determining a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

33. A method for selecting a subject for a cancer treatment, the method comprising:(a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; andDBl / 161946556.2 129Attorney Docket No.: BID-014PC / 110304-5014-PC(b) selecting the subject for a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

34. A method of treating cancer, the method comprising:(a) evaluating a biological sample obtained from a subject for the expression or activity of pogo transposable element derived with KRAB domain (POGK), wherein the biological sample comprises or is suspected to comprise at least one cancer cell; and(b) administering to the subject for a POGK therapy if the biological sample has a reduced expression or activity of POGK compared to a second biological sample from the subject that does not comprise or is suspected not to comprise a cancer cell, a second biological sample from another subject that is not suffering from cancer and / or a standard that has been determined as representing a cancer negative sample.

35. The method of any one of claims 30-34, wherein the POGK therapy is or comprises an isolated nucleic acid that is capable of inducing exon skipping in a pogo transposable element derived with KRAB domain (POGK) mRNA.

36. The method of claim 35, wherein the nucleic acid is an antisense oligonucleotide (ASO).

37. The method of claim 36, wherein the ASO inhibits the formation of mRNA encoding POGK isoform 2, and / or the ASO inhibits the formation of mRNA encoding POGK isoform 1 , and / or promotes the formation of mRNA encoding POGK isoform 1.

38. The method of claim 36 or claim 37, wherein the ASO promotes the inclusion of exon 2 of POGK in the mRNA, optionally wherein the ASO promotes the formation of an mRNA comprising exons 2, 3, 4, 5, and 6.

39. A kit comprising the pharmaceutical composition of any one of claims 1 -38 with instructions for use in modulating and / or modifying and / or delivering the isolated nucleic acid.DBl / 161946556.2 130Attorney Docket No.: BID-014PC / 110304-5014-PC40. A composition comprising an antisense oligonucleotide, wherein the composition attenuates, weakens, reduces, decreases, or ablates the splicing that results in isoform 2 of POGK, wherein: the antisense oligonucleotide comprises at least one 2'-O-methylation modifications and at least six internal phosphorothioate deoxyribonucleotides; and the antisense oligonucleotide is about 15 to about 20 nucleotides in length.41 . A method of treating cancer in a subject in need thereof, the method comprising: i) administering to the subject a pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises an isolated nucleic acid, small molecule, or protein inhibiting pogo transposable element derived with KRAB domain (POGK) isoform 1 or (ii) contacting a cell with a pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises an isolated nucleic acid, small molecule, or protein inhibitor of pogo transposable element derived with KRAB domain (POGK) isoform 1 and administering the cell to the subject.DBl / 161946556.2 131

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