Antisense cancer therapeutics with alkylating agents

Abstract

This invention relates to agents, compositions, and methods for use in treating or ameliorating symptoms of cancer. Exemplary synergistic therapies include the use of antisense oligonucleotide agents for suppressing expression of TGF-β2 in combination with alkylating agents or HDAC inhibitors. Patients can be distinguished by reduced histone deacetylases. Additional therapies include the use of antisense oligonucleotide agents for suppressing expression of TGF-β2 for patients who have (a) low genomic methylation and / or (b) high TGF-β2 expression. Diagnostic information and methods are provided with histone deacetylases.

Description

Docket No. 018988-024WO1ANTISENSE CANCER THERAPEUTICS WITH ALKYLATING AGENTSSEQUENCE LISTING

[0001] This application includes a sequence listing submitted electronically as an ST.26 file created on October 6, 2025, named 018988-024W01_SL.xml, which is 40,573 bytes in size.TECHNICAL FIELD

[0002] This invention relates to agents, compositions, and methods for use in treating or ameliorating symptoms of cancer. Exemplary synergistic therapies include the use of antisense oligonucleotide agents for suppressing expression of TGF-P2, both alone and in combination with DNA alkylating agents and biomarkers. Clinical outcomes further supply diagnostic information and methods.BACKGROUND

[0003] Cancer is a complex pathology involving multiple variant cellular pathways. Because of this complexity, many anti-cancer drugs have limited or partial therapeutic effectiveness.

[0004] Drawbacks of conventional therapies include lack of efficacy as determined by overall survival. In some cases, surgical resection is not possible because of anatomical location of tumors.

[0005] Further drawbacks of conventional therapies include significant unwanted side effects such as killing healthy cells in addition to killing cancer cells.

[0006] Additional drawbacks of anti-cancer agents include high toxicity at required levels of therapeutic administration. In some cases, a monotherapy may not be a feasible strategy because the presence and level of therapeutic targets may vary.

[0007] In diagnosis and prognosis of cancer, drawbacks of existing biomarkers include failure to implicate a significant association of the biomarkers with cancer activity or a specific therapeutic.

[0008] What is needed are agents, compositions and methods for cancer diseases to increase efficacy and reduce toxicity and unwanted side effects. Therapy involving a combination of active agents can improve therapeutic effects and clinical outcomes. Moreover, the guidance of biomarkers can be a powerful tool for improving therapies.Docket No. 018988-024WO1

[0009] Therapeutic compositions of different agents are needed to supply significant anticancer effects and which can improve efficacy, reduce side effects and reduce adverse health effects.

[0010] There is an urgent need for cancer therapies that can reduce dosages of the agents to spare subjects from adverse effects. There is a need for improved guidance for use of such compositions by using appropriate biomarkers to select synergistic effects of the agents and compositions.

[0011] Further, there is an urgent need for new diagnostic information and methods for cancer such as biomarker methods for guiding a specific therapeutic, as well as detecting independent associations with cancer.BRIEF SUMMARY

[0012] This invention provides agents, compositions, and methods for use in treating or ameliorating the symptoms of cancer. Exemplary synergistic therapies include the use of antisense oligonucleotide agents for suppressing expression of TGF-P2, both alone and in combination with alkylating agents. Cancer therapeutic modalities of this disclosure include selecting patients and cancers for therapy via biomarkers to improve outcomes.

[0013] This invention further provides methods and products for diagnosis and prognosis of cancer disease states based on studies of clinical outcomes.

[0014] Embodiments of this invention further contemplate utilizing therapeutic antisense agents for suppressing high levels of TGF-P2 expression, which may be done in combination with alkylating agents and by selecting patients based on levels of certain biomarkers.

[0015] In some embodiments, methods and therapeutic strategies of this invention can include increased guidance for successful patient outcomes using appropriate biomarkers to select synergistic effects of the compositions and agents.

[0016] Further embodiments of this invention include suppressing high levels of TGF-P2 expression alone and selecting patients based on a biomarker to improve clinical outcomes.

[0017] In certain embodiments, this invention provides cancer therapies with antisense oligonucleotide agents for suppressing expression of TGF-P2 in combinationDocket No. 018988-024WO1 with alkylating agents. The combination can advantageously reduce the required dose of alkylating agents for effective results in treating or ameliorating the symptoms of cancer. In certain embodiments, the combination can advantageously increase the survival of treated patients while maintaining the same required dose. In some embodiments, subjects can be selected who have (a) high TGF-P2 expression and / or (b) low histone deacetylases. Selecting subjects with these characteristics can surprisingly improve clinical outcomes. The antisense oligonucleotide agents can suppress expression of TGF-P2 to low levels for treating or ameliorating the symptoms of cancer. Selecting subjects who have low levels of histone deacetylases has been discovered as a useful biomarker for surprisingly improved outcomes in such therapies.

[0018] In additional embodiments, this invention provides cancer therapies with antisense oligonucleotide agents for suppressing expression of TGF-P2, where the subjects are selected who have (a) low genomic DNA methylation and (b) high TGF-P2 expression. Selecting subjects with these characteristics can surprisingly improve clinical outcomes. The antisense oligonucleotide agents can suppress expression of TGF-P2 to low levels for treating or ameliorating the symptoms of cancer. Genomic DNA methylation has been discovered as a useful biomarker for surprisingly improved outcomes in such therapies.

[0019] This invention further supplies new diagnostic methods and products for cancer. Methods of this invention include collecting data relating to an individual subject or a group of subjects to generate a dataset comprising mRNA levels or protein levels of the subjects for TGF-P2 and one or both of HDAC1 and HDAC2.

[0020] Embodiments of this invention include the following:

[0021] A composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0022] A composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for use in the preparation of a medicament for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.Docket No. 018988-024WO1

[0023] A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering to the subject a therapeutically sufficient amount of a composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent; wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0024] The composition or method above, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

[0025] The composition or method above, wherein the low histone deacetylases are reduced expression of one or both of HD AC 1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

[0026] The composition or method above, wherein the subjects are less than 59 years of age.

[0027] The composition or method above, wherein the DNA alkylating agent is an SN1 orSN2 alkylating agent.

[0028] The composition or method above, wherein the DNA alkylating agent is procarbazine, dacarbazine, carbamazepine, temozolomide, streptozotocin, 1 -methyl- 1 -nitrosourea, N-methyl- N’-nitro-N-nitrosoguanidine, methyl methanesulfonate, N,N-dimethyl-D-erythro-sphingosine, melphalan, melphalan flufenamide, busulfan, mechlorethamine, cyclophosphamide, ifosfamide, bendamustine, chlorambucil, carmustine, lomustine, altretamine, thiotepa, or a salt or ester form of any of the foregoing, or a combination thereof.

[0029] The composition or method above, wherein the DNA alkylating agent is carboplatin, cisplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin tetranitrate, or a salt or ester form of any of the foregoing, or a combination thereof.

[0030] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

[0031] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre-mRNA or mRNA and 18-21 nucleotides in length.Docket No. 018988-024WO1

[0032] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.

[0033] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

[0034] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-0Me ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

[0035] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a triantenarry N-acteyl- galactosamine.

[0036] The composition or method above, wherein the composition comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

[0037] The composition or method above, wherein the composition is substantially free of excipients.

[0038] The composition or method above, wherein the composition is stable for at least 14 days in carrier at 37°C.

[0039] The composition or method above, wherein the composition is administered by infusion or injection.

[0040] The composition or method above, wherein the composition increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

[0041] A medical product comprising an antisense agent for suppressing expression of TGF- P2 and a DNA alkylating agent for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.Docket No. 018988-024WO1

[0042] A medical product comprising an antisense agent for suppressing expression of TGF- P2 and a DNA alkylating agent in the preparation of a medicament for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0043] A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering to the subject a therapeutically sufficient amount of an antisense agent for suppressing expression of TGF-P2; and administering to the subject a DNA alkylating agent; wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0044] The medical product or method above, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

[0045] The medical product or method above, wherein the low histone deacetylases are reduced expression of one or both of HD AC 1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

[0046] The medical product or method above, wherein the subjects are less than 59 years of age.

[0047] The medical product or method above, wherein the antisense agent for suppressing expression of TGF-P2 and the DNA alkylating agent are administered concurrently, simultaneously, sequentially, or separately in time.

[0048] The medical product or method above, wherein the DNA alkylating agent is an SN1 or SN2 alkylating agent.

[0049] The medical product or method above, wherein the DNA alkylating agent is procarbazine, dacarbazine, carbamazepine, temozolomide, streptozotocin, 1 -methyl- 1- nitrosourea, N-methyl-N’-nitro-N-nitrosoguanidine, methyl methanesulfonate, N,N-dimethyl-D- erythro-sphingosine, melphalan, melphalan flufenamide, busulfan, mechlorethamine, cyclophosphamide, ifosfamide, bendamustine, chlorambucil, carmustine, lomustine, altretamine, thiotepa, or a salt or ester form of any of the foregoing, or a combination thereof.

[0050] The medical product or method above, wherein the DNA alkylating agent is carboplatin, cisplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin,Docket No. 018988-024WO1 picoplatin, satraplatin, triplatin tetranitrate, or a salt or ester form of any of the foregoing, or a combination thereof.

[0051] The medical product or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

[0052] The medical product or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre-mRNA or mRNA and 18-21 nucleotides in length.

[0053] The medical product or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.

[0054] The medical product or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

[0055] The medical product or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-0Me ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

[0056] The medical product or method above, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a triantenarry N-acteyl- galactosamine.

[0057] The medical product or method above, wherein the antisense agent and the DNA alkylating agent are singly formulated, and wherein the antisense agent formulation comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof, and wherein the DNA alkylating agent formulation comprises an oral or intravenous dosage form.

[0058] The medical product or method above, wherein the medical product or method increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.Docket No. 018988-024WO1

[0059] The medical product or method above, wherein the composition is combined with a standard of care treatment for the cancer.

[0060] A composition comprising an antisense agent for suppressing expression of TGF-P2 for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression.

[0061] A composition comprising an antisense agent for suppressing expression of TGF-P2 in the preparation of a medicament for treating or ameliorating the symptoms of cancer in subjects who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression.

[0062] A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: selecting subjects who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression; and administering a therapeutically sufficient amount of an agent for suppressing expression of TGF-P2 to the subjects.

[0063] The composition or method above, wherein the cancer is pancreatic cancer, ovarian cancer, stomach cancer, brain or spinal cancer, glioma, glioblastoma, or diffuse midline glioma (DMG).

[0064] The composition or method above, wherein the low genomic DNA methylation is reduced genomic DNA methylation below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

[0065] The composition or method above, wherein the subjects are less than 59 years of age.

[0066] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

[0067] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre-mRNA or mRNA and 18-21 nucleotides in length.

[0068] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.Docket No. 018988-024WO1

[0069] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

[0070] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-0Me ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

[0071] The composition or method above, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a triantenarry N-acteyl- galactosamine.

[0072] The composition or method above, wherein the composition comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

[0073] The composition or method above, wherein the composition is substantially free of excipients.

[0074] The composition or method above, wherein the composition is administered by infusion or injection.

[0075] The composition or method above, wherein the composition increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

[0076] The composition or method above, wherein the composition or method is combined with a standard of care treatment for the cancer.

[0077] A method for collecting data, the method comprising: obtaining data relating to an individual subject or a group of subjects to generate a dataset comprising mRNA levels or protein levels of the subjects for TGF-P2 and one or both of HDAC1 and HDAC2.

[0078] The method above, comprising obtaining one or more clinical parameters from the subjects selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

[0079] The method above, wherein the subjects are less than 59 years of age.Docket No. 018988-024WO1

[0080] A method for diagnosing or prognosing pancreatic, stomach, or ovarian cancer in an individual subject, the method comprising: obtaining data for a control group of subjects to generate a control dataset comprising mRNA levels or protein levels of the subjects for TGF-P2 and one or both of HDAC1 and HDAC2, wherein the control group of subjects have previously been diagnosed with pancreatic, stomach, or ovarian cancer; obtaining data for a sample from the individual subject to generate an individual dataset comprising mRNA levels or protein levels of the individual subject for TGF-P2 and one or both of HD AC 1 and HDAC2; comparing the dataset of the individual subject to the dataset of the control group; and determining differences between the datasets of the individual subject and the control group, where the differences meet a threshold for indicating pancreatic, stomach, or ovarian cancer in the individual subject.

[0081] The method above, comprising obtaining a value for one or more clinical parameters for the subjects of the control group and the individual subject, the clinical parameters selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

[0082] The method above, comprising diagnosing or prognosing cancer disease progression in the subject.

[0083] The method above, comprising treating the subject for cancer by administering an anti -cancer drug.

[0084] A method for diagnosing or prognosing pancreatic, stomach, or ovarian cancer in an individual subject, the method comprising: obtaining data for control human mRNA levels or protein levels for TGF-P2 and one or both of HD AC 1 and HDAC2; obtaining data for an individual human subject comprising mRNA levels or protein levels for TGF-P2 and one or both of HDAC1 and HDAC2; comparing the data for the individual human subject to the control human mRNA levels or protein levels; and determining differences between the data for the individual human subject and the control human mRNA levels or protein levels exceeding a threshold for indicating pancreatic, stomach, or ovarian cancer in the individual subject.Docket No. 018988-024WO1

[0085] The method above, wherein the control human mRNA levels or protein levels are obtained from a control group of subjects, wherein the control group comprises: a group of subjects who do not have pancreatic, stomach, or ovarian cancer; a group of subjects who do not present any symptoms of pancreatic, stomach, or ovarian cancer; a monitored group of subjects who do not have pancreatic, stomach, or ovarian cancer at any time; a tested group of subjects who have a known risk of pancreatic, stomach, or ovarian cancer; a patient group of subjects who have been diagnosed with an early stage of pancreatic, stomach, or ovarian cancer; or a patient group of subjects who have been diagnosed with a late stage of pancreatic, stomach, or ovarian cancer; wherein any of the above control groups have been, or have not been treated for cancer.

[0086] The method above, comprising obtaining a value for one or more clinical parameters for the subjects of the control group and the individual human subject, the clinical parameters selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

[0087] The method above, comprising diagnosing or prognosing pancreatic, stomach, or ovarian cancer disease, or pancreatic, stomach, or ovarian cancer disease progression in the subject.

[0088] The method above, comprising treating the individual human subject for pancreatic, stomach, or ovarian cancer by administering an anti-cancer drug.

[0089] A medical product kit for determining expression levels of TGF-P2 and one or both of HDAC1 and HDAC2 in a subject with a blood sample, a CSF sample, a fresh frozen sample, a snap frozen sample, an FFPE sample, or a biopsy sample, the medical product kit comprising reagents for specifically detecting the expression levels.

[0090] The medical product kit above for use in diagnosing or prognosing pancreatic, stomach, or ovarian cancer.

[0091] A composition comprising an antisense agent for suppressing expression of TGF-P2 and a carrier for use in treating or ameliorating the symptoms of cancer in a subject in combination with an HDAC inhibitor, wherein the subject has TGF-P2 expression above a median level of subjects with the same disease.Docket No. 018988-024WO1

[0092] A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering a composition comprising an antisense agent for suppressing expression of TGF-P2 and a carrier to the subject; and administering an HD AC inhibitor to the subject; wherein the agents are singly-formulated and administered concurrently, simultaneously, sequentially, or separately in time; wherein the subject has TGF-P2 expression above a median level of subjects with the same disease.

[0093] The composition or method above, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0094] The composition or method above, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

[0095] The composition or method above, wherein the low histone deacetylases are reduced expression of one or both of HD AC 1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

[0096] The composition or method above, wherein the subjects are less than 59 years of age.

[0097] The composition or method above, wherein the HDAC inhibitor is vorinostat, valproic acid, belinostat, panobinostat, tucidinostat, or a salt or ester form of any of the foregoing, or a combination thereof.

[0098] The composition or method above, wherein the agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A* T*G* T*C*T*A* T* T* T*T*G*T*A SEQ ID NO: 1.

[0099] The composition or method above, comprising a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

[0100] The composition or method above, wherein the agents or medicament are for infusion or injection, or are an oral dosage form.

[0101] The composition or method above, wherein the administration of the agent for suppressing expression of TGF-P2 comprises two or more cycles of 7-day or 4-dayDocket No. 018988-024WO1 intravenous infusion, wherein successive cycles are separated by a 10-day treatment- free interval, and wherein the dosage is 50 to 330 mg / m2 / day.

[0102] The composition or method above, wherein the agents, use or method increases a survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

[0103] The composition or method above, wherein the composition or method is combined with a standard of care treatment for cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0104] FIG. 1 shows results of a study of clinical outcomes in glioblastoma. It was found that age was strongly associated with overall survival (OS) for glioblastoma and that younger patients had three times longer overall survival as compared to older patients.

[0105] FIG. 2 shows results of a study of clinical outcomes in glioblastoma. It was found that methylation level of TGF-P2 (HM27) was associated with increased overall survival (OS) for glioblastoma patients. FIG. 2 shows that high methylation level of TGF-P2 was associated with significant improvement in overall survival.

[0106] FIG. 3 shows results of a study of clinical outcomes in PDAC pancreatic cancer. It was found that methylation level of TGF-P2 (as HM450) was associated with increased survival for pancreatic cancer patients. FIG. 3 shows that high methylation level of TGF-P2 was associated with significant improvement in disease free survival.

[0107] FIG. 4 shows results of a study of clinical outcomes in ovarian cancer. It was found that older age was associated with decreased overall survival for ovarian cancer patients.

[0108] FIG. 5 shows results of a study of clinical outcomes in ovarian cancer. It was found that methylation level of TGF-P2 (HM27) was associated with increased overall survival for ovarian cancer patients. FIG. 5 shows that high methylation level of TGF- P2 was associated with significant improvement in overall survival.

[0109] FIG. 6 shows results of a study of clinical outcomes in glioblastoma. It was found that older age was associated with decreased survival for glioblastoma patients.

[0110] FIG. 7 shows results of a study of clinical outcomes in glioblastoma. It was found that methylation level of TGF-P2 was associated with increased survival for glioblastoma patients. FIG. 7 shows that high methylation level of TGF-P2 was associated with significant improvement in survival.Docket No. 018988-024WO1

[0111] FIG. 8 shows results of a study of clinical outcomes in glioblastoma. It was found that methylation level of TGF-P2 was associated with increased survival for younger glioblastoma patients, as compared to older patients. FIG. 8 shows that high methylation level of TGF-P2 was associated with significant and surprisingly improved survival for younger glioblastoma patients.

[0112] FIG. 9 shows results of a study of clinical outcomes in glioblastoma. It was found that age was associated with increased survival for younger glioblastoma patients, as compared to older patients.

[0113] FIG. 10 shows results of clinical trial outcomes in high grade glioma. It was found that age was associated with increased survival for younger high grade glioma patients, as compared to older patients.

[0114] FIG. 11 shows results of clinical trial outcomes in high grade glioma. It was found that treatment with antisense agent OT-101 provided increased median survival. The improvement in survival for treatment with antisense agent OT-101 was found to be surprisingly greater for younger versus older glioma patients.

[0115] FIG. 12 shows results of clinical trial outcomes in high grade glioma. It was found that treatment with antisense agent OT-101 provided increased median survival. The improvement in survival for treatment with antisense agent OT-101 was found to be surprisingly greater for younger versus older high grade glioma patients.

[0116] FIG. 13 shows results of a study of clinical outcomes in pancreatic cancer. It was found that age was associated with increased median survival for younger pancreatic cancer patients, as compared to older patients. FIG. 13 shows that age was associated with improved survival for younger pancreatic cancer patients.

[0117] FIG. 14 shows results of a study of clinical outcomes in pancreatic cancer. It was found that methylation level of TGF-P2 was associated with increased survival for pancreatic cancer patients. FIG. 14 shows that high methylation level of TGF-P2 was associated with significant and surprisingly improved survival for pancreatic cancer patients.

[0118] FIG. 15 shows results of a study of clinical outcomes in pancreatic cancer. It was found that methylation level of TGF-P2 was associated with increased survival for younger pancreatic cancer patients. FIG. 15 shows that high methylation level of TGF-Docket No. 018988-024WO1P2 was associated with significantly and surprisingly improved survival for younger pancreatic cancer patients.

[0119] FIG. 16 shows results of a study of clinical outcomes in ovarian cancer. It was found that age was associated with increased survival for ovarian cancer patients. FIG. 16 shows that age was associated with significantly improved survival for younger ovarian cancer patients.

[0120] FIG. 17 shows results of a study of clinical outcomes in ovarian cancer. It was found that methylation level of TGF-P2 was associated with increased survival for ovarian cancer patients. FIG. 17 shows that high methylation level of TGF-P2 was associated with significant and surprisingly improved survival for ovarian cancer patients.

[0121] FIG. 18 shows results of a study of clinical outcomes in PDAC pancreatic cancer. FIG. 18 shows that for PDAC pancreatic cancer patients with HDAC1 below median level, patients with low TGF-P2 expression achieved significantly and surprisingly increased overall survival.

[0122] FIG. 19 shows results of a study of clinical outcomes in stomach cancer. FIG.19 shows that for stomach cancer patients with HDAC2 below median level, patients with low TGF-P2 expression achieved significantly and surprisingly increased overall survival.

[0123] FIG. 20 shows results of a study of clinical outcomes in ovarian cancer. FIG.20 shows that for ovarian cancer patients with HDAC1 below median level, patients with low TGF-P2 expression achieved significantly and surprisingly increased overall survival.

[0124] FIG. 21 shows results of clinical trial outcomes in pancreatic cancer treated with OT-101. It was found that age was associated with increased survival for younger patients, as compared to older patients. FIG. 21 shows that age was associated with significantly improved survival for younger pancreatic cancer patients.DETAILED DESCRIPTION OF THE DISCLOSURE

[0125] This invention relates to agents, compositions, and methods for use in treating or ameliorating symptoms of cancer. Exemplary synergistic therapies include active agents for suppressing expression of TGF-P2, both alone and in combination with alkylating agents. One or more biomarkers can be used to select subjects for treatment.Docket No. 018988-024WO1

[0126] This invention provides agents, compositions, and methods for use in treating or ameliorating the symptoms of cancer. Exemplary synergistic therapies include the use of antisense oligonucleotide agents for suppressing expression of TGF-P2, both alone and in combination with alkylating agents. Cancer therapeutic modalities of this disclosure include selecting patients and cancers for therapy via biomarkers to improve outcomes.

[0127] This invention further supplies new diagnostic information and methods for cancer.

[0128] Embodiments of this invention contemplate utilizing therapeutic antisense agents for suppressing high levels of TGF-P2 expression, which may be done in combination with alkylating agents and by selecting patients based on levels of certain biomarkers.

[0129] In some embodiments, methods and therapeutic strategies of this invention can include increased guidance for successful patient outcomes using appropriate biomarkers to select synergistic effects of the compositions and agents.

[0130] Further embodiments of this invention include suppressing high levels of TGF-P2 expression alone and selecting patients based on a biomarker to improve clinical outcomes.

[0131] In certain embodiments, this invention provides cancer therapies with antisense oligonucleotide agents for suppressing expression of TGF-P2 in combination with alkylating agents. The combination can advantageously reduce the required dose of alkylating agents for effective results in treating or ameliorating the symptoms of cancer. In some embodiments, subjects can be selected who have (a) high TGF-P2 expression and (b) low histone deacetylases. Selecting subjects with these characteristics can surprisingly improve clinical outcomes. The antisense oligonucleotide agents can suppress expression of TGF-P2 to low levels for treating or ameliorating the symptoms of cancer. Selecting subjects who have low levels of histone deacetylases has been discovered as a useful biomarker for surprisingly improved outcomes in such therapies.

[0132] In additional embodiments, this invention provides cancer therapies with antisense oligonucleotide agents for suppressing expression of TGF-P2, where the subjects are selected who have (a) low genomic DNA methylation and / or (b) high TGF-Docket No. 018988-024WO1P2 expression. Selecting subjects with these characteristics can surprisingly improve clinical outcomes. The antisense oligonucleotide agents can suppress expression of TGF-P2 to low levels for treating or ameliorating the symptoms of cancer. Genomic DNA methylation has been discovered as a useful biomarker for surprisingly improved outcomes in such therapies.

[0133] In some embodiments, one or more biomarkers can be used to select subjects for the method, agent or use. The methods, compositions and agents can be used in combination with chemotherapy and standard-of-care therapies for the same cancer.

[0134] In certain embodiments, cancers of this disclosure to be treated may include any of brain or spinal cancer, glioma, glioblastoma, diffuse intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), diffuse hemispheric glioma, or leptomeningeal or brain metastasis, or wherein cells of the cancer exhibit somatic mutations comprising H3-K27M, H2-K27M, or H3-G34 genomic variants.

[0135] In some embodiments, cancers of this disclosure to be treated may have cells which exhibit somatic mutations comprising H3-K27M, H2-K27M, or H3-G34 genomic variants.

[0136] In further embodiments, cancers of this disclosure to be treated may have cells which exhibit somatic mutations comprising H3-K27M genomic variants.

[0137] In certain embodiments, cancers of this disclosure to be treated may include diffuse midline gliomas with cells which exhibit somatic mutations comprising H3- K27M genomic variants.

[0138] In some embodiments, diagnoses, genomic variants or biomarker transcript levels can be obtained or measured by methods and / or facilities known and / or compiled in the art, including next-generation sequencing, RNA-Seq, whole exome sequencing, tissue biopsy, liquid biopsy, and radiological methods.

[0139] As used herein, the terms patient and subject are interchangeable. A subject in need of cancer therapy as described herein may be a human or animal subject.

[0140] As used herein, the terms TGF-P2, TGFB2, TGFb2, TGF-b2, and TGF-B2 are synonymous.

[0141] As used herein, the term agent can refer to one or more active compounds, a combination of active compounds, or a composition containing one or more active compounds and a carrier, and / or a solvent, and / or any number of excipients. In someDocket No. 018988-024WO1 embodiments, the composition may be a pharmaceutical composition. In certain embodiments, the composition may be a pharmaceutical composition containing a therapeutically effective amount of one or more active compounds. Formulations of active agents can be determined by those skilled in the art. Some examples of excipients are given in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975, and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980. Methods for determining a therapeutically effective amount of a compound are known in the art.Anti-cancer methods and compositions

[0142] This disclosure provides methods for treating or ameliorating the symptoms of cancer which may include a step or steps for selecting subjects for treatment who have elevated expression of TGF-P2 along with certain levels of guiding biomarkers. Surprisingly improved overall survival for cancer patients can be achieved.

[0143] Methods of this disclosure for treating or ameliorating the symptoms of cancer may include a step or steps for selecting subjects for treatment who have low histone deacetylases. Low histone deacetylases can be determined as known in the art. In certain embodiments, low histone deacetylases can be determined as being below a median value for a group of subjects.

[0144] Methods of this disclosure for treating or ameliorating the symptoms of cancer may include a step or steps for selecting subjects for treatment who have low genomic DNA methylation. Genomic DNA methylation can be determined as known in the art, for example, using INFINIUM HM27 and HM450. In certain embodiments, genomic DNA methylation can be determined as being above a median value for a group of subjects.

[0145] This invention includes methods for treating or ameliorating the symptoms of cancer in subjects in need. The method may comprise administering a therapeutically sufficient amount of an agent for suppressing expression of TGF-P2 to the subject; and administering a therapeutically sufficient amount of a DNA alkylating agent to the subject; wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases. Cancers which may be treated in these methods includeDocket No. 018988-024WO1 pancreatic cancer, ovarian cancer, stomach cancer, brain or spinal cancer, glioma, glioblastoma, and diffuse midline glioma (DMG).

[0146] In some embodiments, this invention further provides methods for treating or ameliorating the symptoms of cancer in subjects in need by selecting subjects who have (a) low genomic DNA methylation and / or (b) high TGF-P2 expression; and administering a therapeutically sufficient amount of an agent for suppressing expression of TGF-P2 to the subjects. Cancers which may be treated in these methods include pancreatic cancer, ovarian cancer, stomach cancer, brain or spinal cancer, glioma, glioblastoma, and diffuse midline glioma (DMG).

[0147] In additional aspects, agents used in combination for treating cancer can be administered concurrently, simultaneously, sequentially, or separately in time.Human TGF-P2-specific phosphorothioate antisense oligodeoxynucleotide

[0148] An antisense oligonucleotide (ASO) can be a single-stranded deoxyribonucleotide, which may be complementary to an mRNA target. The antisense therapy may downregulate a molecular target, which may be achieved by induction of RNase H endonuclease activity that cleaves the RNA-DNA heteroduplex with a significant reduction of the target gene translation. Other ASO mechanisms can include inhibition of 5’ cap formation, alteration of splicing process such as splice-switching, and steric hindrance of ribosomal activity.

[0149] Antisense therapeutic strategies can utilize single-stranded DNA oligonucleotides that inhibit protein production by mediating the catalytic degradation of a target mRNA, or by binding to sites on mRNA needed for translation. Antisense oligonucleotides can be designed to target the viral RNA genome or viral transcripts. Antisense oligonucleotides can provide an approach for identifying potential targets, and therefore represent potential therapeutics.

[0150] Antisense oligonucleotides can be small synthetic pieces of single-stranded DNA that may be 15-30 nucleotides in length. An ASO may specifically bind to a complementary DNA / RNA sequence by Watson-Crick hybridization and once bound to the target RNA, inhibit the translational processes either by inducing cleavage mechanisms or by inhibiting mRNA maturation. An ASO may selectively inhibit geneDocket No. 018988-024WO1 expression with specificity. Chemical modifications of DNA or RNA can be used to increase stability.

[0151] For example, modifications can be introduced in the phosphodiester bond, the sugar ring, and the backbone. ASO antiviral agents may block translational processes either by (i) ribonuclease H (RNAse H) or RNase P mediated cleavage of mRNA or (ii) by sterically (non- bonding) blocking enzymes that are involved in the target gene translation. Human TGF-P2-specific phosphorothioate antisense oligodeoxynucleotide (OT-101; AP 12009; Trabedersen), hereafter referred to as OT-101 or AP 12009, is intended to reduce the level of TGF-P2 protein in malignant gliomas, and thereby delay the progression of disease.

[0152] Antisense oligodeoxynucleotides are short strings of DNA that are designed to downregulate gene expression by interfering with the translation of a specific encoded protein at the mRNA level. OT-101 is a synthetic 18-mer phosphorothioate oligodeoxynucleotide (S-ODN) where all 3 ’-5’ linkages are modified to phosphorothioates. The molecular formula is Ci77H208N6oNai7094Pi7Si7 and the molecular weight 6, 143 g / mol. OT-101 can be designed to be complementary to a specific sequence of human TGF-P2 mRNA following expression of the gene.

[0153] OT-101 can be supplied as a lyophilized powder in 50 mL glass vials in three different quantities. Each vial is identified by the name of the investigational product, trial number, dosing group, mode of application, quantity of OT-101 contained (in mg), total volume after dissolving (in mL) and resulting concentration (in pM), name of sponsor, name of manufacturer, batch number, vial number, storage temperature, and expiry date. The study medication can be provided in closed units, packaged separately for each concentration. The packages may contain the appropriate vial(s) and all necessary components of the application system (i.e., syringes, tube, and filter). OT- 101 lyophilized powder can be dissolved in isotonic (0.9%) aqueous sodium chloride prior to use.

[0154] Examples of agents of this disclosure for inhibiting or suppressing expression of TGF-P2 include TGF-P2-specific antisense oligonucleotides given in SEQ ID NOs: l- 40 in Table 1.Docket No. 018988-024WO1Table 1 : TGF-P2-specific antisense oligonucleotidesDocket No. 018988-024WO1

[0155] In Table 1, each asterisk (*) represents a phosphorothioate linkage.

[0156] The sequences of Table 1 can be chemically-modified to provide active variants thereof, LNA variants thereof, as well as gapmer variants thereof, as known in the art. The sequences of Table 1 can be used in any combination as active agents, such as pooling combinations.

[0157] It is understood that additional antisense oligonucleotides of this disclosure can be constructed based on the TGF-P2 gene sequence.

[0158] In some embodiments, an agent of antisense sequences can be gapmers formed by adding 1 to 5 protected ribo-nucleotides on each flank of the phosphorothioate deoxy-nucleotide sequences in Table 1. For example, the ribonucleotides can be protected with 2’-0Me, 2’-OEt, or 2’-0-M0E substituents, or with LNA, cMOE, or cEt bridges, as well as phosphorothioate linkages.

[0159] In some embodiments, an agent of antisense sequences can be a n-M-n RNA(2’-OMe)*-DNA*-RNA(2’-OMe)* gapmer, where n is from 3-7 and M is from 6- 12. In certain embodiments, the gapmer can be a 3-10-3 or 5-10-5 LNA*-DNA*-LNA* or cEt*-DNA*-cEt* gapmer (* designates phosphorothioate linkages).

[0160] Embodiments of this invention further include pharmaceutical compositions for inhibiting or suppressing expression of TGF-P, or for treating or ameliorating the symptoms of cancer in a human or animal. The pharmaceutical compositions may contain a TGF-P suppressing agent, pharmaceutically acceptable salts forms, esters, polymorphs or stereoisomers thereof, and any combination thereof, as well as a carrier. The TGF-P suppressing agent may be selected from TGF-P2-specific antisense oligonucleotides. The carrier may be sterile water for injection, saline, isotonic saline, or a combination thereof.

[0161] Importantly, a composition of this disclosure may be substantially free of excipients. Compositions of this invention which are substantially free of excipients have been found to be surprisingly stable in a carrier. In some embodiments, the composition may be stable for at least 14 days, or at least 21 days, or at least 28 days in a carrier at 37°C.Docket No. 018988-024WO1

[0162] In additional embodiments, a pharmaceutical composition for infusion may contain less than 1% by weight of excipients, or less than 0.5% by weight of excipients, or less than 0.1% by weight of excipients.QT-101 antisense oligonucleotide

[0163] The API trabedersen / OT-101 is a synthetic 18-mer S-ODN consisting of the bases adenine (A), thymine (T), guanine (G), and cytosine (C), with all 3'-5' linkages modified to phosphorothioates. The thioate modification can make the drug more resistant to degradation, resulting in an increased stability in vitro and in vivo. Its molecular structure (nucleotide sequence) can be designed to be complementary to a specific sequence of human transforming growth factor-beta 2 (TGF-P2) mRNA. This sequence can be selected among related molecules for its superior chemical and structural properties, biological activity, and specificity to achieve the best antisense effects in vitro and in vivo.

[0164] The chemical structure, exemplary of the phosphorothioate moieties (C-A-G), and the physical characteristics of trabedersen are shown in Table 2.Table 2: Chemical and Physical Characteristics of TrabedersenDocket No. 018988-024WO1

[0165] The IMP can be supplied as a sterile lyophilizate for solution for infusion in 50H glass vials (primary container) containing 7.37 mg trabedersen (intratumoral treatment) and in 20R glass vials (primary container) containing 250 mg trabedersen (intravenous treatment), respectively. No excipients may be in the finished drug product. Glass vials are commonly used for parenterals. Sterile rubber stoppers appropriate for lyophilization can seal the glass vial. The stopper may be sealed with a crimping capsule that includes a colored flip-off cap. For clinical use, each vial can be provided within a white-colored folding box to protect the vials from light exposure and damage during transport. Both the glass vials and the folding boxes can be labeled according to local requirements. The primary and secondary containers of the closure system can fulfill international quality standards for the packaging of sterile solid drug products for injections.Alkylating agents

[0166] Examples of DNA alkylating agents for treating cancer are known in the art.

[0167] Some examples include procarbazine, dacarbazine, temozolomide, mitozolomide, streptozotocin, 1 -methyl- 1 -nitrosourea, N-methyl-N’-nitro-N- nitrosoguanidine, methyl methanesulfonate, N,N-dimethyl-D-erythro-sphingosine, melphalan, melphalan flufenamide, busulfan, mechlorethamine, cyclophosphamide, ifosfamide, bendamustine, chlorambucil, carmustine, lomustine, altretamine, thiotepa, and a salt or ester form of any of the foregoing, and a combination thereof.

[0168] Some examples of DNA alkylating agents for treating cancer include platinum-based compounds such as cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin tetranitrate, and a salt or ester form of any of the foregoing, and a combination thereof. Such platinum-based compounds are typically classified as alkylating agents.

[0169] Formulations and dosage forms of alkylating agents are known in the art for systemic delivery, intravenous injection or infusion, or in some cases oral delivery.Docket No. 018988-024WO1Standard of care treatment for cancer

[0170] A standard of care treatment for a cancer may include one or more additional medicaments comprising a targeted cancer drug, a cancer growth blocker, or an EGFR inhibitor.

[0171] A standard of care treatment for a cancer may include one or more additional medicaments comprising erlotinib, gefitinib, afatinib, osimertinib, dacomitininb, and combinations thereof.

[0172] A standard of care treatment for a cancer may include one or more additional medicaments comprising a targeted cancer drug selected from bevacizumab, everolimus, belzutifan, dabrafenib, trametinib, and combinations thereof.

[0173] A standard of care treatment for a cancer may include one or more additional medicaments comprising a cancer growth blocker selected from an angiogenesis inhibitor, a histone deacetylase inhibitor, a hedgehog blocker, an mTOR inhibitor, a p53 inhibitor, a PARP inhibitor, a proteasome inhibitor, a tyrosine kinase inhibitor, and combinations thereof.Dosage of active agents

[0174] An antisense oligonucleotide may be supplied as a lyophilized powder in glass vials in different quantities. Antisense oligonucleotide lyophilized powder can be dissolved in isotonic (0.9%) aqueous sodium chloride prior to use.

[0175] In some examples and embodiments, an antisense oligonucleotide agent may be administered or used by infusion at a dose of 4 pl / min at a concentration level of 10 pM on Days 1 to 7, or at a dose of 20 pM on Days 1 to 7, or at a dose of 40 pM on Days 1 to 7, or at a dose of 80 pM on Days 1 to 7.

[0176] In some examples and embodiments, an antisense oligonucleotide agent may be administered or used by infusion at a rate of 4 pl / min, or 2-8 pl / min, at a concentration level of 2 pM on Days 1 to 7, or at a dose of 4 pM on Days 1 to 7, or at a dose of 8 pM on Days 1 to 7, or at a dose of 10 pM on Days 1 to 7.

[0177] In some embodiments, an antisense oligonucleotide agent may be administered by injection at concentrations of 61.43 mg / ml (10 pM), Img / ml, 7.35 mg / ml, 15 mg / ml, or 18.23 mg / ml.Docket No. 018988-024WO1

[0178] In some embodiments, alkylating agents may be administered or used at a dosage of 1 mg / kg, or 5 mg / kg, or 10 mg / kg, or 20 mg / kg, or 30 mg / kg, or 40 mg / kg, or 50 mg / kg, or 100 mg / kg, or 200 mg / kg. In certain embodiments, alkylating agents may be administered or used at a dosage of 0.1 mg / kg, or 0.2 mg / kg, or 0.25 mg / kg, or 0.3 mg / kg, or 0.4 mg / kg, or 0.5 mg / kg, or 0.75 mg / kg, or 0.8 mg / kg, or 0.9 mg / kg.Alkylating agents may be administered or used at a dosage range of 0.1-100 mg / kg, or 0.2-75 mg / kg, or 0.5-50 mg / kg, or 1-30 mg / kg, or 2-25 mg / kg.

[0179] In further embodiments, an antisense oligonucleotide agent may be administered or used by infusion, either singly, in combination with a formulationcompatible drug, or in combination with standard of care therapies.

[0180] An agent of this disclosure may be a pharmaceutically-acceptable salt, salt polymorph, ester, or isomer, and one or more pharmaceutically acceptable excipients. Excipients may comprise any one or more pharmaceutically acceptable excipients selected from diluents, stabilizers, disintegrants and anticaking agents. In some embodiments, the excipients may comprise any one or more of microcrystalline cellulose, polysorbate 80, crospovidone, croscarmellose sodium, and magnesium stearate.

[0181] A pharmaceutical compositions may contain an active agent as well as a pharmaceutically-acceptable carrier. The carrier may be sterile water for injection, saline, isotonic saline, or a combination thereof.

[0182] Importantly, a composition of this disclosure may be substantially free of excipients. Compositions of this invention which are substantially free of excipients can be surprisingly stable in a carrier. In some embodiments, the composition may be stable for at least 14 days, or at least 21 days, or at least 28 days in a carrier at 37°C.

[0183] In additional embodiments, a pharmaceutical composition for infusion may contain less than 1% by weight of excipients, or less than 0.5% by weight of excipients, or less than 0.1% by weight of excipients.

[0184] Embodiments of this invention further contemplate therapeutic modalities in which a composition of this invention is administered or utilized in combination with a standard of care therapy for the disease.Docket No. 018988-024WO1

[0185] In further embodiments, a therapeutically effective amount of an antisense agent can be from 0.1 to 3000 mg per day, or 1 to 1000 mg per day, or 2 to 500 mg per day, or 2 to 200 mg per day.

[0186] In certain embodiments, a formulation of an antisense agent can have a concentration of from 0.05 to 50 pM, or 0.1 to 25 pM, or 0.1 to 10 pM, or 0.1 to 7.5 pM, or 0. 1 to 5 pM.

[0187] In certain embodiments, a method for using an antisense agent can use an effective dosage amount of from 1 to 1000 mg / m2 / day, or from 1 to 500 mg / m2 / day, or from 1 to 250 mg / m2 / day, or from 1 to 100 mg / m2 / day, or from 1 to 50 mg / m2 / day. Mean human body surface area can be about 1.6 to 1.9 m2.

[0188] In additional embodiments, a method for using an antisense agent can use an effective dosage amount of from 0.05 to 40 mg / kg / day, or from 0.1 to 30 mg / kg / day, or from 0.2 to 20 mg / m2 / day, or from 0.3 to 10 mg / m2 / day, or from 0.5 to 5 mg / m2 / day. Mean human body weight can be about 60 kg.

[0189] In certain embodiments, agents of this disclosure may be prepared from a lyophilized powder of the agent.

[0190] In some examples and embodiments, an agent may be administered or used by injection or infusion at a dose of 4 pl / min at a dose level of 10 pM on the Days 1 to 7, or at a dose of 20 pM on Days 1 to 7, or at a dose of 40 pM on Days 1 to 7, or at a dose of 80 pM on Days 1 to 7.

[0191] In certain embodiments, an antisense oligonucleotide may be supplied as a sterile lyophilizate for solution prior to administration in 20R glass vials with a quantity of 250 mg / vial. The lyophilizate may be reconstituted aseptically in sterile, preservative-free isotonic NaCl solution. Antisense oligonucleotide solution can be administered every 14 days using a portable pump system as a continuous i.v. infusion on days 4-7 according to a 4-days-on, 10-days-off schedule. A schedule may be 7 d on / 7d off and 4 d on / 10 d off scheduling. A dose may be 40, 80, 160, 140, 190, 250, 330 mg.

[0192] In certain embodiments, an agent may be administered or used by injection or infusion at a dose of 40, 80, 160, 140, 190, 250, 330 mg / m2on Days 1 to 7, or at a dose of 40, 80, 160, 140, 190, 250, 330 mg / m2on Days 1 to 4.Docket No. 018988-024WO1

[0193] In some examples and embodiments, an agent may be administered or used by injection or infusion at a rate of 4 pl / min, or 2-8 pl / min, at a dose level of 2 pM on Days 1 to 7, or at a dose of 4 pM on Days 1 to 7, or at a dose of 8 pM on Days 1 to 7, or at a dose of 10 pM on Days 1 to 7.

[0194] As used herein, the term chemically-modified can refer to LNA variants and gapmer variants. Antisense agents of this disclosure can be used by pooling in a formulation, or used in any combination.Methods and compositions for cancer

[0195] The agents and compositions of this invention can be used for treating cancer or ameliorating the symptoms of cancer in a human subject or animal in need. The agents may be prepared in a pharmaceutical composition for injection or infusion. Some actives can be prepared in oral forms.

[0196] A pharmaceutical composition for injection or infusion may be administered in a therapeutically sufficient amount to the subject.

[0197] Pharmaceutical agents or active substances of this disclosure may be dissolved or suspended in a physiological solvent or in any other appropriate solvent. The agents may be in the form of a free base, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of these compounds. The above mentioned agents as well as combinations thereof can be used in the apparatuses, methods, kits, combinations, and compositions herein described.

[0198] Compositions of this invention can contain compounds to be infused to the subject formulated as an injectable formulation, for example, an aqueous solution or suspension of the compounds suitable for intravenous delivery. When preparing the composition for injection, particularly for intravenous delivery, illustratively, the continuous phase comprises an aqueous solution of tonicity modifiers, buffered to a pH below 7.4, for example, or below 7 or below 6.6, for example. The tonicity modifiers comprise, for example, sodium chloride, glucose, mannitol, trehalose, glycerol, or other pharmaceutical agents that renders the osmotic pressure of the formulation isotonic with blood.Docket No. 018988-024WO1

[0199] The system of this invention can contain a preservative added to the formulation. A preservative includes benzalkonium chloride, propylparaben, butylparaben, chlorobutanol, belizyl alcohol, phenol, sodium benzoate, or EDTA.

[0200] The composition of this disclosure can contain a pharmaceutically acceptable carrier. The carrier materials that can be employed in making the compositions of the present invention are any of those commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with the pharmaceutical agent and the release pro-file properties of the desired dosage form.

[0201] A composition of this invention can contain excipients such as are given in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975, and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y, 1980.

[0202] Embodiments of this invention contemplate compositions including an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases. An antisense agent can suppress expression of TGF-P2 and a DNA alkylating agent can suppress histone deacetylases. Thus, such compositions treat or ameliorate cancer in the subject who, after treatment, will have low TGF-P2 expression and low histone deacetylases. Such compositions can be used in methods for treating or ameliorating the symptoms of cancer in a subject in need by administering to the subject a therapeutically sufficient amount of a composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0203] In some embodiments, the compositions and methods can be used for treating glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

[0204] In certain aspects, low histone deacetylases are reduced expression of one or both of HDAC1 and HDAC2 below median of a control. High TGF-P2 expression is TGF-P2 expression above median of a control.

[0205] In certain embodiments, the subjects may be less than 59 years of age.Docket No. 018988-024WO1

[0206] In further embodiments, this invention provides a medical product comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0207] A medical product can be used in methods for treating or ameliorating the symptoms of cancer in a subject in need by administering to the subject a therapeutically sufficient amount of an antisense agent for suppressing expression of TGF-P2 and administering to the subject a DNA alkylating agent, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0208] The medical product can be used for cancers including glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer. Using the medical product or method, the antisense agent for suppressing expression of TGF-P2 and the DNA alkylating agent can be administered concurrently, simultaneously, sequentially, or separately in time.

[0209] Embodiments of this invention also contemplate compositions containing an antisense agent for suppressing expression of TGF-P2 for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression. Such compositions can be used in methods for treating or ameliorating the symptoms of cancer in a subject in need by selecting subjects who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression, and administering a therapeutically sufficient amount of an agent for suppressing expression of TGF-P2 to the subject. The cancer may be pancreatic cancer, ovarian cancer, stomach cancer, brain or spinal cancer, glioma, glioblastoma, or diffuse midline glioma (DMG).Diagnosis and prognosis of cancer

[0210] This disclosure relates to methods and products for assessing, diagnosing, monitoring, and selecting treatment for a cancer disease.

[0211] Methods and products of this invention for assessing, diagnosing, monitoring, and selecting treatment for a cancer are advantageous because cancer disease and progression is highly variable and unpredictable.Docket No. 018988-024WO1

[0212] This invention further supplies new diagnostic methods and products for cancer. Methods of this invention include collecting data relating to an individual subject or a group of subjects to generate a dataset comprising mRNA levels or protein levels of the subjects for TGF-P2 and one or both of HDAC1 and HDAC2.

[0213] Additional data may include clinical parameters such as age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking. These methods and products can be surprisingly accurate for subjects less than 59 years of age. Subjects may than be treated for cancer by administering an anti-cancer drug.

[0214] In some embodiments, methods and products of this disclosure can be used for diagnosing or prognosing pancreatic, stomach, or ovarian cancer disease, or pancreatic, stomach, or ovarian cancer disease progression in the subject. Methods and medical products can involve determining expression levels of TGF-P2 and one or both of HDAC1 and HDAC2 using a blood sample, a CSF sample, a fresh frozen sample, a snap frozen sample, an FFPE sample, or a biopsy sample with reagents for specifically detecting the expression levels.

[0215] In certain aspects, a method for diagnosing or prognosing pancreatic, stomach, or ovarian cancer in an individual subject can be performed by obtaining data for control human mRNA levels or protein levels for TGF-P2 and one or both of HDAC1 and HDAC2. Similar data for an individual human subject can be compared to data for control human mRNA levels or protein levels. Thus, differences can be determined between the individual human subject and the control levels which exceed a threshold for indicating pancreatic, stomach, or ovarian cancer in the individual subject.

[0216] Methods and products of this invention may utilize control human mRNA levels or protein levels obtained from a control group of subjects. A control group may include any of: patients previously diagnosed with cancer who have not been treated for the cancer; patients previously diagnosed with cancer who have been treated for the cancer; a group of subjects who do not have cancer; a group of subjects who do not present any symptoms of cancer; a monitored group of subjects who do not have cancer at any time; a tested group of subjects who have a known risk of cancer; a patient group of subjects who have been diagnosed with an early stage of cancer;Docket No. 018988-024WO1 and / or a patient group of subjects who have been diagnosed with a late stage of cancer.

[0217] In further aspects, any of the control groups may include therapy naive subjects, or subjects who have been treated for cancer.

[0218] Methods and products for diagnosing or prognosing cancer may include clinical parameters such as age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

[0219] In certain embodiments, methods and products of this invention for diagnosing or prognosing cancer may be used for pancreatic, stomach, or ovarian cancer disease, or pancreatic, stomach, or ovarian cancer disease progression.

[0220] In some embodiments, methods and products of this invention for diagnosing or prognosing cancer may include treating an individual human subject for a specific cancer such as pancreatic, stomach, or ovarian cancer. Treatment of a cancer can include anti-cancer drugs, surgery, standard of care therapies and elements thereof, biopsy, debulking surgery, scopic surgery, bariatric surgery, or resection.

[0221] In further embodiments, methods and products of this invention for diagnosing or prognosing cancer may include a medical product kit for determining expression levels of TGF- P2 and one or both of HD AC 1 and HDAC2 in a subject with a blood sample, a CSF sample, a fresh frozen sample, a snap frozen sample, an FFPE sample, or a biopsy sample. A medical product kit may comprise reagents for specifically detecting the expression levels.

[0222] In certain embodiments, a sample may include any biological sample such as cells, body fluid, whole blood or any fraction thereof, serum, plasma, red blood cells, white blood cells, endothelial cells, tissue biopsies, and other bodily fluids.

[0223] In some embodiments, a biomarker can be HDAC1, for example, reference NM_004964.3.

[0224] In some embodiments, a biomarker can be HDAC2, for example, reference NM_001527.4.

[0225] In some embodiments, a biomarker can be TGF-P2 NCBI Reference Sequence NM_003238.3.Docket No. 018988-024WO1Therapeutics with antisense agents and HDAC inhibitors

[0226] Embodiments of this invention contemplate compositions containing an antisense agent for suppressing expression of TGF-P2 and a carrier for use in treating or ameliorating the symptoms of cancer in a subject in combination with an HDAC inhibitor, wherein the subject has TGF-P2 expression above a median level of subjects with the same disease.

[0227] In some embodiments, this invention provides methods for treating or ameliorating the symptoms of cancer in a subject in need, by administering a composition comprising an antisense agent for suppressing expression of TGF-P2 and a carrier to the subject, and administering an HDAC inhibitor to the subject, wherein the agents are singly-formulated and administered concurrently, simultaneously, sequentially, or separately in time, and wherein the subject has TGF-P2 expression above a median level of subjects with the same disease.

[0228] Embodiments involving antisense agents and HDAC inhibitors can use an HDAC inhibitor selected from vorinostat, valproic acid, belinostat, panobinostat, tucidinostat, or a salt or ester form of any of the foregoing, or a combination thereof.

[0229] Embodiments involving antisense agents and HDAC inhibitors can use OT- 101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

[0230] In some embodiments, such compositions may contain a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

[0231] In further aspects, an antisense agent can be for infusion or injection.

[0232] In certain aspects, an HDAC inhibitors may be an oral dosage form, or may be for infusion or injection.

[0233] In certain embodiments, administration of the agent for suppressing expression of TGF-P2 may include two or more cycles of 7-day or 4-day intravenous infusion, wherein successive cycles are separated by a 10-day treatment-free interval, and wherein the dosage is 50 to 330 mg / m2 / day.

[0234] Embodiments of this invention employing therapeutic combination of an antisense agent for suppressing expression of TGF-P2 and an HDAC inhibitor can increase a survival rate of a subject at month 6, 12, 18, 24, 30, or 36.Docket No. 018988-024WO1

[0235] Embodiments of this invention employing therapeutic combination of an antisense agent for suppressing expression of TGF-P2 and an HDAC inhibitor can be combined with a standard of care treatment for cancers such as glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer. Standard of care treatment for cancers can include anti-cancer drugs, surgery, biopsy, debulking surgery, scopic surgery, bariatric surgery, and resection.

[0236] In some embodiments, an HDAC inhibitor may be administered or used at a daily oral dosage of up to 200 mg, or 300 mg, or 400 mg.

[0237] In further embodiments, an HDAC inhibitor may be administered or used at a dosage of 1 mg / kg, or 5 mg / kg, or 10 mg / kg, or 20 mg / kg, or 30 mg / kg, or 40 mg / kg, or 50 mg / kg, or 100 mg / kg, or 200 mg / kg.

[0238] In certain embodiments, an HDAC inhibitor may be administered or used at a dosage of 0.1 mg / kg, or 0.2 mg / kg, or 0.25 mg / kg, or 0.3 mg / kg, or 0.4 mg / kg, or 0.5 mg / kg, or 0.75 mg / kg, or 0.8 mg / kg, or 0.9 mg / kg.

[0239] HDAC inhibitors may be administered or used at a dosage range of 0.1-100 mg / kg, or 0.2-75 mg / kg, or 0.5-50 mg / kg, or 1-30 mg / kg, or 2-25 mg / kg, or 1-10 mg / kg.

[0240] Numbered embodiments of this invention include the following:

[0241] (1) A composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0242] (2) A composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for use in the preparation of a medicament for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0243] (3) A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering to the subject a therapeutically sufficient amount of a composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent;Docket No. 018988-024WO1 wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0244] (4) The composition or method of any of embodiments 1-3, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

[0245] (5) The composition or method of any of embodiments 1-4, wherein the low histone deacetylases are reduced expression of one or both of HDAC1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

[0246] (6) The composition or method of any of embodiments 1-5, wherein the subjects are less than 59 years of age.

[0247] (7) The composition or method of any of embodiments 1-6, wherein the DNA alkylating agent is an SN1 or SN2 alkylating agent.

[0248] (8) The composition or method of any of embodiments 1-7, wherein the DNA alkylating agent is procarbazine, dacarbazine, carbamazepine, temozolomide, streptozotocin, 1 -methyl- 1 -nitrosourea, N-methyl-N’-nitro-N-nitrosoguanidine, methyl methanesulfonate, N,N-dimethyl-D-erythro-sphingosine, melphalan, melphalan flufenamide, busulfan, mechlorethamine, cyclophosphamide, ifosfamide, bendamustine, chlorambucil, carmustine, lomustine, altretamine, thiotepa, or a salt or ester form of any of the foregoing, or a combination thereof.

[0249] (9) The composition or method of any of embodiments 1-8, wherein the DNA alkylating agent is carboplatin, cisplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin tetranitrate, or a salt or ester form of any of the foregoing, or a combination thereof.

[0250] (10) The composition or method of any of embodiments 1-9, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2- specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

[0251] (11) The composition or method of any of embodiments 1-10, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2- specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre-mRNA or mRNA and 18-21 nucleotides in length.Docket No. 018988-024WO1

[0252] (12) The composition or method of any of embodiments 1-11, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2- specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.

[0253] (13) The composition or method of any of embodiments 1-12, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

[0254] (14) The composition or method of any of embodiments 1-13, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-OMe ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

[0255] (15) The composition or method of any of embodiments 1-14, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a triantenarry N-acteyl-galactosamine.

[0256] (16) The composition or method of any of embodiments 1-15, wherein the composition comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

[0257] (17) The composition or method of any of embodiments 1-16, wherein the composition is substantially free of excipients.

[0258] (18) The composition or method of any of embodiments 1-17, wherein the composition is stable for at least 14 days in carrier at 37°C.

[0259] (19) The composition or method of any of embodiments 1-18, wherein the composition is administered by infusion or injection.

[0260] (20) The composition or method of any of embodiments 1-19, wherein the composition increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

[0261] (21) A medical product comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.Docket No. 018988-024WO1

[0262] (22) A medical product comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent in the preparation of a medicament for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0263] (23) A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering to the subject a therapeutically sufficient amount of an antisense agent for suppressing expression of TGF-P2; and administering to the subject a DNA alkylating agent; wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

[0264] (24) The medical product or method of any of embodiments 21-23, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

[0265] (25) The medical product or method of any of embodiments 21-24, wherein the low histone deacetylases are reduced expression of one or both of HDAC1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

[0266] (26) The medical product or method of any of embodiments 21-25, wherein the subjects are less than 59 years of age.

[0267] (27) The medical product or method of any of embodiments 21-26, wherein the antisense agent for suppressing expression of TGF-P2 and the DNA alkylating agent are administered concurrently, simultaneously, sequentially, or separately in time.

[0268] (28) The medical product or method of any of embodiments 21-27, wherein the DNA alkylating agent is an SN1 or SN2 alkylating agent.

[0269] (29) The medical product or method of any of embodiments 21-28, wherein the DNA alkylating agent is procarbazine, dacarbazine, carbamazepine, temozolomide, streptozotocin, 1 -methyl- 1 -nitrosourea, N-methyl-N’-nitro-N-nitrosoguanidine, methyl methanesulfonate, N,N-dimethyl-D-erythro-sphingosine, melphalan, melphalan flufenamide, busulfan, mechlorethamine, cyclophosphamide, ifosfamide, bendamustine, chlorambucil, carmustine, lomustine, altretamine, thiotepa, or a salt or ester form of any of the foregoing, or a combination thereof.Docket No. 018988-024WO1

[0270] (30) The medical product or method of any of embodiments 21-29, wherein the DNA alkylating agent is carboplatin, cisplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin tetranitrate, or a salt or ester form of any of the foregoing, or a combination thereof.

[0271] (31) The medical product or method of any of embodiments 21-30, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF- P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

[0272] (32) The medical product or method of any of embodiments 21-31, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF- P2-specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre- mRNA or mRNA and 18-21 nucleotides in length.

[0273] (33) The medical product or method of any of embodiments 21-32, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF- P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.

[0274] (34) The medical product or method of any of embodiments 21-33, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

[0275] (35) The medical product or method of any of embodiments 21-34, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-OMe ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

[0276] (36) The medical product or method of any of embodiments 21-35, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a triantenarry N-acteyl-galactosamine.

[0277] (37) The medical product or method of any of embodiments 21-36, wherein the antisense agent and the DNA alkylating agent are singly formulated, and whereinDocket No. 018988-024WO1 the antisense agent formulation comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof, and wherein the DNA alkylating agent formulation comprises an oral or intravenous dosage form.

[0278] (38) The medical product or method of any of embodiments 21-37, wherein the medical product or method increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

[0279] (39) The medical product or method of any of embodiments 21-38, wherein the composition is combined with a standard of care treatment for the cancer.

[0280] (40) A composition comprising an antisense agent for suppressing expression of TGF-P2 for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression.

[0281] (41) A composition comprising an antisense agent for suppressing expression of TGF-P2 in the preparation of a medicament for treating or ameliorating the symptoms of cancer in subjects who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression.

[0282] (42) A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: selecting subjects who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression; and administering a therapeutically sufficient amount of an agent for suppressing expression of TGF-P2 to the subjects.

[0283] (43) The composition or method of any of embodiments 40-42, wherein the cancer is pancreatic cancer, ovarian cancer, stomach cancer, brain or spinal cancer, glioma, glioblastoma, or diffuse midline glioma (DMG).

[0284] (44) The composition or method of any of embodiments 40-43, wherein the low genomic DNA methylation is reduced genomic DNA methylation below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

[0285] (45) The composition or method of any of embodiments 40-44, wherein the subjects are less than 59 years of age.Docket No. 018988-024WO1

[0286] (46) The composition or method of any of embodiments 40-45, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2- specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

[0287] (47) The composition or method of any of embodiments 40-46, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2- specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre-mRNA or mRNA and 18-21 nucleotides in length.

[0288] (48) The composition or method of any of embodiments 40-47, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2- specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.

[0289] (49) The composition or method of any of embodiments 40-48, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

[0290] (50) The composition or method of any of embodiments 40-49, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-OMe ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

[0291] (51) The composition or method of any of embodiments 40-50, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a triantenarry N-acteyl-galactosamine.

[0292] (52) The composition or method of any of embodiments 40-51, wherein the composition comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

[0293] (53) The composition or method of any of embodiments 40-52, wherein the composition is substantially free of excipients.

[0294] (54) The composition or method of any of embodiments 40-53, wherein the composition is administered by infusion or injection.Docket No. 018988-024WO1

[0295] (55) The composition or method of any of embodiments 40-54, wherein the composition increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

[0296] (56) The composition or method of any of embodiments 40-55, wherein the composition or method is combined with a standard of care treatment for the cancer.

[0297] (57) A method for collecting data, the method comprising: obtaining data relating to an individual subject or a group of subjects to generate a dataset comprising mRNA levels or protein levels of the subjects for TGF-P2 and one or both of HDAC1 and HDAC2.

[0298] (58) The method of embodiment 57, comprising obtaining one or more clinical parameters from the subjects selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

[0299] (59) The method of embodiments 57 or 58, wherein the subjects are less than59 years of age.

[0300] (60) A method for diagnosing or prognosing pancreatic, stomach, or ovarian cancer in an individual subject, the method comprising: obtaining data for a control group of subjects to generate a control dataset comprising mRNA levels or protein levels of the subjects for TGF-P2 and one or both of HDAC1 and HDAC2, wherein the control group of subjects have previously been diagnosed with pancreatic, stomach, or ovarian cancer; obtaining data for a sample from the individual subject to generate an individual dataset comprising mRNA levels or protein levels of the individual subject for TGF-P2 and one or both of HDAC1 and HDAC2; comparing the dataset of the individual subject to the dataset of the control group; and determining differences between the datasets of the individual subject and the control group, where the differences meet a threshold for indicating pancreatic, stomach, or ovarian cancer in the individual subject.

[0301] (61) The method of embodiment 60, comprising obtaining a value for one or more clinical parameters for the subjects of the control group and the individual subject, the clinical parameters selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.Docket No. 018988-024WO1

[0302] (62) The method of embodiments 60 or 61, comprising diagnosing or prognosing cancer disease progression in the subject.

[0303] (63) The method of any of embodiments 60-62, comprising treating the subject for cancer by administering an anti-cancer drug.

[0304] (64) A method for diagnosing or prognosing pancreatic, stomach, or ovarian cancer in an individual subject, the method comprising: obtaining data for control human mRNA levels or protein levels for TGF-P2 and one or both of HD AC 1 and HDAC2; obtaining data for an individual human subject comprising mRNA levels or protein levels for TGF-P2 and one or both of HDAC1 and HDAC2; comparing the data for the individual human subject to the control human mRNA levels or protein levels; and determining differences between the data for the individual human subject and the control human mRNA levels or protein levels exceeding a threshold for indicating pancreatic, stomach, or ovarian cancer in the individual subject.

[0305] (65) The method of embodiment 64, wherein the control human mRNA levels or protein levels are obtained from a control group of subjects, wherein the control group comprises: a group of subjects who do not have pancreatic, stomach, or ovarian cancer; a group of subjects who do not present any symptoms of pancreatic, stomach, or ovarian cancer; a monitored group of subjects who do not have pancreatic, stomach, or ovarian cancer at any time; a tested group of subjects who have a known risk of pancreatic, stomach, or ovarian cancer; a patient group of subjects who have been diagnosed with an early stage of pancreatic, stomach, or ovarian cancer; or a patient group of subjects who have been diagnosed with a late stage of pancreatic, stomach, or ovarian cancer; wherein any of the above control groups have been, or have not been treated for cancer.

[0306] (66) The method of embodiments 64 or 65, comprising obtaining a value for one or more clinical parameters for the subjects of the control group and the individualDocket No. 018988-024WO1 human subject, the clinical parameters selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

[0307] (67) The method of any of embodiments 64-66, comprising diagnosing or prognosing pancreatic, stomach, or ovarian cancer disease, or pancreatic, stomach, or ovarian cancer disease progression in the subject.

[0308] (68) The method of any of embodiments 64-67, comprising treating the individual human subject for pancreatic, stomach, or ovarian cancer by administering an anti-cancer drug.

[0309] (69) A medical product kit for determining expression levels of TGF-P2 and one or both of HDAC1 and HDAC2 in a subject with a blood sample, a CSF sample, a fresh frozen sample, a snap frozen sample, an FFPE sample, or a biopsy sample, the medical product kit comprising reagents for specifically detecting the expression levels.

[0310] (70) The medical product kit of embodiment 69 for use in diagnosing or prognosing pancreatic, stomach, or ovarian cancer.

[0311] (71) A composition comprising an antisense agent for suppressing expression of TGF-P2 and a carrier for use in treating or ameliorating the symptoms of cancer in a subject in combination with an HDAC inhibitor, wherein the subject has TGF-P2 expression above a median level of subjects with the same disease.

[0312] (72) A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering a composition comprising an antisense agent for suppressing expression of TGF-P2 and a carrier to the subject; and administering an HDAC inhibitor to the subject; wherein the agents are singly-formulated and administered concurrently, simultaneously, sequentially, or separately in time; wherein the subject has TGF-P2 expression above a median level of subjects with the same disease.

[0313] (73) The composition or method of any of embodiments 71-72, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.Docket No. 018988-024WO1

[0314] (74) The composition or method of any of embodiments 71-73, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

[0315] (75) The composition or method of any of embodiments 71-74, wherein the low histone deacetylases are reduced expression of one or both of HDAC1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

[0316] (76) The composition or method of any of embodiments 71-75, wherein the subjects are less than 59 years of age.

[0317] (77) The composition or method of any of embodiments 71-76, wherein theHDAC inhibitor is vorinostat, valproic acid, belinostat, panobinostat, tucidinostat, or a salt or ester form of any of the foregoing, or a combination thereof.

[0318] (78) The composition or method of any of embodiments 71-77, wherein the agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

[0319] (79) The composition or method of any of embodiments 71-78, comprising a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

[0320] (80) The composition or method of any of embodiments 71-79, wherein the agents or medicament are for infusion or injection, or are an oral dosage form.

[0321] (81) The composition or method of any of embodiments 71-80, wherein the administration of the agent for suppressing expression of TGF-P2 comprises two or more cycles of 7-day or 4-day intravenous infusion, wherein successive cycles are separated by a 10-day treatment-free interval, and wherein the dosage is 50 to 330 mg / m2 / day.

[0322] (82) The composition or method of any of embodiments 71-81, wherein the agents, use or method increases a survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

[0323] (83) The composition or method of any of embodiments 71-82, wherein the composition or method is combined with a standard of care treatment for cancer.Docket No. 018988-024WO1

[0324] All publications including patents, patent application publications, and nonpatent publications referred to in this description, as well as the sequence listing are each expressly incorporated herein by reference in their entirety for all purposes.

[0325] Section headings used herein are for convenience of organization and are not to be construed as limiting the subject matter described herein or any combination thereof. This invention includes any combinations or mixtures of the features, materials, elements, or limitations of the various illustrative components, examples, and claimed embodiments.

[0326] Although the foregoing disclosure has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the artisan that certain changes and modifications are comprehended by the disclosure and may be practiced without undue experimentation within the scope of the appended claims. This invention includes all such additional embodiments, equivalents, and modifications.

[0327] The designations of agents, compounds and structures of this disclosure are meant to encompass all possible isomers, stereoisomers, diastereomers, enantiomers, and / or optical isomers that would be understood to exist for the specified structure, including any mixture, racemic or otherwise, thereof.EXAMPLES

[0328] Example 1. FIG. 1 shows results of a study of clinical outcomes in glioblastoma (CBioPortal). It was found that age was strongly associated with overall survival (OS) for glioblastoma patients. FIG. 1 shows that younger age was associated with significant improvement in overall survival (p value <1 e-10). FIG. 1 shows that younger patients had three times longer overall survival as compared to older patients. Median survival was 23.1 months for younger patients and 7.7 months for older patients. Results are shown in Table 3.Table 3 : Overall survival (OS) for glioblastoma patientsDocket No. 018988-024WO1

[0329] Example 2 FIG. 2 shows results of a study of clinical outcomes in glioblastoma (CBioPortal). It was found that methylation level of TGF-P2 (as HM27) was associated with increased overall survival (OS) for glioblastoma patients. FIG. 2 shows that high methylation level of TGF-P2 was associated with significant improvement in overall survival (p value 3.391e-4). This result was surprising because TGF-pi and TGF-P3 were not associated with increased overall survival.

[0330] Median survival was 13.8 months for patients with low methylation level of TGF-P2 (A) and 18.3 months for patients with high methylation level of TGF-P2 (D). Results are shown in Table 4.Table 4: Overall survival (OS) for glioblastoma patients

[0331] Example 3. FIG. 3 shows results of a study of clinical outcomes in PDAC pancreatic cancer (CBioPortal). It was found that methylation level of TGF-P2 (as HM450) was associated with surprisingly increased survival for pancreatic cancer patients. FIG. 3 shows that high methylation level of TGF-P2 was associated with significant improvement in disease free survival (p value 8.883e-3). This result was surprising because TGF-pi and TGF-P3 were not associated with increased survival.

[0332] Median survival was 12 months for patients with low methylation level of TGF-P2 (A) and over 42 months for patients with high methylation level of TGF-P2 (D). Results are shown in Table 5.Table 5: Overall survival (OS) for pancreatic cancer patients

[0333] Example 4. FIG. 4 shows results of a study of clinical outcomes in ovarian cancer (CBioPortal). It was found that younger age was associated with increasedDocket No. 018988-024WO1 overall survival for ovarian cancer patients. FIG. 4 shows that younger age was associated with significant improvement in overall survival (p value <le-10). Median survival was 54 months for younger patients and 35 months for older patients. Results are shown in Table 6.Table 6: Overall survival for ovarian cancer patients

[0334] Example 5. FIG. 5 shows results of a study of clinical outcomes in ovarian cancer (CBioPortal). It was found that methylation level of TGF-P2 (as HM27) was associated with increased overall survival for ovarian cancer patients. FIG. 5 shows that high methylation level of TGF-P2 was associated with significant improvement in overall survival (p value 1.734e-3). This result was surprising because TGF-pi and TGF-P3 were not associated with increased overall survival.

[0335] Median survival was 40 months for patients with low methylation level of TGF-P2 (A) and 49 months for patients with high methylation level of TGF-P2 (D). Results are shown in Table 7.Table 7: Overall survival for ovarian cancer patients

[0336] Example 6. FIG. 6 shows results of a study of clinical outcomes in glioblastoma (CBioPortal). It was found that younger age was associated with increased survival for glioblastoma patients. FIG. 6 shows that younger age was associated with significant improvement in median survival of younger patients, as compared to older patients (log-rank p value <le-4). Median survival was 18 months for younger patients and 13 months for older patients. Results are shown in Table 8 and Table 9.Docket No. 018988-024WO1Table 8: Survival for glioblastoma patientsTable 9: Survival for glioblastoma patientsDocket No. 018988-024WO1

[0337] Example 7. FIG. 7 shows results of a study of clinical outcomes in glioblastoma (CBioPortal). It was found that methylation level of TGF-P2 was associated with increased survival for glioblastoma patients. FIG. 7 shows that high methylation level of TGF-P2 was associated with improvement in survival (Mantel-Cox log rank p value 0.0013). Results are shown in Table 10 and Table 11.Table 10: Survival for glioblastoma patientsTablet 1 : Survival for glioblastoma patientsDocket No. 018988-024WO1

[0338] Example 8. FIG. 8 shows results of a study of clinical outcomes in glioblastoma (CBioPortal). It was found that methylation level of TGF-P2 was associated with increased survival for younger glioblastoma patients, as compared to older patients. FIG. 8 shows that high methylation level of TGF-P2 was associated with significantly improved survival for younger glioblastoma patients (Mantel-Cox log rank p value <0.0001). Results are shown in Table 12 and Table 13.Table 12: Survival for glioblastoma patientsTable 13 : Survival for glioblastoma patientsDocket No. 018988-024WO1

[0339] Example 9. FIG. 9 shows results of a study of clinical outcomes in glioblastoma (CBioPortal). It was found that age was associated with increased survival for younger glioblastoma patients, as compared to older patients. FIG. 9 shows that age was associated with significant improvement in survival for younger glioblastoma patients (Mantel-Cox log rank p value <0.0001). Median survival was 18 months for younger patients and 11 months for older patients. Results are shown in Table 14 and Table 15.Table 14: Survival for glioblastoma patientsTable 15 : Survival for glioblastoma patientsDocket No. 018988-024WO1

[0340] Example 10. FIG. 10 shows results of clinical trial outcomes in high grade glioma (G004, NCT00431561, Grade III anaplastic astrocytoma (AA) or Grade IV GBM). It was found that age was associated with increased survival for younger high grade glioma patients, as compared to older patients. FIG. 10 shows that age was associated with significantly improved survival for younger glioblastoma patients (Mantel-Cox log rank p value <0.0001). Median survival was 485 days for younger patients, which was double the 247 days found for older patients. Results are shown in Table 16 and Table 17.Table 16: Survival for high grade glioma patientsDocket No. 018988-024WO1Table 17: Survival for high grade glioma patients

[0341] G004 clinical trial (NCT00431561) confirmed that suppression of TGF-P2 expression resulted in improved overall survival. G004 was a multi-national, multicenter, open-label interventional clinical study on patients with R / R HGG. The study was multinational, open-label, randomized, and active controlled. Patients were randomized in a 1 : 1 : 1 ratio using a centralized randomization procedure to treatment with either 10 mM OT-101, 80 mM OT-101, or standard chemotherapy.

[0342] Main inclusion criteria were: male or female patients between 18 and 75 years of age with a reference neuropathology-confirmed diagnosis of recurrent / refractory AA or GBM, Karnofsky performance status (KPS) / >70% at baseline, with tumor lesions ^50 cm3, and a measurable enhancing tumor lesion in MRI with a diameter ^4.5 cm.

[0343] Main exclusion criteria were: patients with tumor surgery within the last 2 weeks, radiotherapy within 8 weeks, chemotherapy within 4 weeks, or a baseline MRI showing a significant mass effect. In order to be eligible for the study, patients had to be consenting adults with a R / R HGG (Grade III anaplastic astrocytoma (AA), Grade IV GBM) with supratentorial localization and a measurable target lesion. The diagnosis was histopathologically confirmed before the start of treatments. Patients had to have an expected life expectancy of >3 months and a baseline Karnofsky Performance Status (KPS) score >70%. Patients who had recent tumor resection within 14 days prior to study entry were excluded, as were patients receiving radiation therapy within 8 weeks prior to randomization. Treatment with chemotherapy, hormone therapy, or any other therapies with established or suggested antitumor effects had to be finished 4-6 weeks (nitrosoureas only) before randomization. No prior stereotactic radiosurgery, interstitial brachytherapy, TGF-P2-targeting therapy, or antitumor vaccination were allowed.Patients who had received another investigational agent within 30 days prior to randomization were not eligible.Docket No. 018988-024WO1

[0344] In order to isolate the clinical single agent anti-HGG activity of OT101, no other cancer treatments, standard or experimental (including but not limited to radiation therapy, chemotherapy, or immunotherapy) were administered unless the patient experienced a progression of disease (PD). Ninety-eight patients (AA: 30; GBM: 68) were randomized to one of the 2 treatment arms of OT101 representing 2 different dose cohorts, namely 2.5 mg / cycle (N = 48) and 19.8 mg / cycle (N = 50). Eight patients discontinued the study after randomization but before the implantation of the catheterport system. Ninety patients (safety population / SP) who underwent surgery for catheter implantation for OT101 and were randomized to one of 2 dose cohorts of OT101 were evaluable for safety. One patient assigned to the low dose cohort discontinued the study after the surgical procedure but before receiving any OT-101 due to procedure related complications.

[0345] There were 89 patients (AA:27; GBM: 62) who had received any amount of OT-101 (modified intent-to-treat / mITT population) and, of these, only 77 (efficacy population) (GBM: 51; AA: 26) received at least the intended minimum number of 4 (median: 7, range: 4-11, mean + SE: 9.8 + 0.3) OT101 treatment cycles. The mITT population included 25 females and 64 males at a median age of 45 (range: 19-73; mean + SE = 46.3 + 1.3) years with a median baseline KPS score of 90 (range 70-100; Mean + SE: 87.6 + 0.9). Patient characteristics and the neuro-oncologic medical history of the patients are shown.

[0346] Fifty-eight patients were Caucasian, whereas 31 were Asian. 62 patients had GBM, and 27 had AA. Forty patients were treated at the low dose level (10 uM concentration in the infusate; 2.5 mg / cycle), and 49 patients were treated at the high dose level (80 uM concentration in the infusate; 19.8 mg / cycle) of OT-101.

[0347] Example 11 FIG. 11 shows results of clinical trial outcomes in high grade glioma (G004, NCT00431561, Grade III anaplastic astrocytoma (AA) or Grade IV GBM). It was found that treatment with antisense agent OT-101 provided increased median survival (Mantel-Cox log rank p value 0.0001). The improvement in survival for treatment with antisense agent OT-101 was found to be surprisingly greater than was found for younger versus older glioma patients. Median survival under treatment with antisense agent OT-101 was 647 days for younger patients, which was triple the 213 days found for older patients treated with OT-101. Moreover, this result was surprisingDocket No. 018988-024WO1 because no significant improvement in survival was observed for use of chemotherapy (best supportive care) alone for the same patient group. Results are shown in Table 18 and Table 19.Table 18: Survival for high grade glioma patientsTable 19: Survival for high grade glioma patients

[0348] Example 12 FIG. 12 shows results of clinical trial outcomes in high grade glioma (G004, NCT00431561, Grade III anaplastic astrocytoma (AA) or Grade IV GBM). It was found that treatment with antisense agent OT-101 provided increased median survival (Mantel-Cox log rank p value 0.0002). The improvement in survival for treatment with antisense agent OT-101 was found to be surprisingly greater than was found for younger versus older high grade glioma patients. Median survival underDocket No. 018988-024WO1 treatment with antisense agent OT-101 was 810 days for younger patients, which was more than triple the 228 days found for older patients treated with OT-101 at a dosage of lOuM. At a dosage of 80uM, median survival under treatment with antisense agent OT-101 was 549 days for younger patients, which was more than triple the 165 days found for older patients treated with OT-101. The surprisingly increased survival using antisense agent OT-101 for younger high grade glioma patients persisted over an OT- 101 dosage range of 10 uM to 80 uM. Results are shown in Table 20 and Table 21.Table 20: Survival for high grade glioma patientsTable 21 : Survival for high grade glioma patients

[0349] Example 13 FIG. 13 shows results of a study of clinical outcomes in pancreatic cancer (CBioPortal). It was found that age was associated with increasedDocket No. 018988-024WO1 median survival for younger pancreatic cancer patients, as compared to older patients.FIG. 13 shows that age was associated with improved survival for younger pancreatic cancer patients. Results are shown in Table 22 and Table 23.Table 22: Survival for pancreatic cancer patientsTable 23 : Survival for pancreatic cancer patients

[0350] Example 14. FIG. 14 shows results of a study of clinical outcomes in pancreatic cancer (CBioPortal). It was found that methylation level of TGF-P2 was associated with increased survival for pancreatic cancer patients. FIG. 14 shows that high methylation level of TGF-P2 was associated with significant and surprisinglyDocket No. 018988-024WO1 improved survival for pancreatic cancer patients (Mantel-Cox p value 0.0409). Median survival was 23 months for patients with high TGF-P2 methylation and 18 months for patients with low TGF-P2 methylation. Results are shown in Table 24 and Table 25.Table 24: Survival for pancreatic cancer patientsTable 25: Survival for pancreatic cancer patients

[0351] Example 15. FIG. 15 shows results of a study of clinical outcomes in pancreatic cancer (CBioPortal). It was found that methylation level of TGF-P2 was associated with increased survival for younger pancreatic cancer patients. FIG. 15Docket No. 018988-024WO1 shows that high methylation level of TGF-P2 was associated with significantly and surprisingly improved survival for younger pancreatic cancer patients (Mantel-Cox p value 0.0302). Median survival for younger patients with high methylation level of TGF-P2 was surprisingly increased as shown by an elevated and elongated tail for such patients in FIG. 15. Results are shown in Table 26 and Table 27.Table 26: Survival for pancreatic cancer patientsTable 27: Survival for pancreatic cancer patients

[0352] Example 16. FIG. 16 shows results of a study of clinical outcomes in ovarian cancer (CBioPortal). It was found that age was associated with survival for ovarian cancer patients. FIG. 16 shows that age was associated with significantly improved survival for younger ovarian cancer patients (Mantel-Cox log rank p value <0.0001).Docket No. 018988-024WO1Median survival was 50 months for younger patients and 38 months for older patients.Results are shown in Table 28 and Table 29.Table 28: Survival for pancreatic cancer patientsTable 29: Survival for pancreatic cancer patients

[0353] Example 17. FIG. 17 shows results of a study of clinical outcomes in ovarian cancer (CBioPortal). It was found that methylation level of TGF-P2 was associated with increased survival for ovarian cancer patients. FIG. 17 shows that highDocket No. 018988-024WO1 methylation level of TGF-P2 was associated with significant and surprisingly improved survival for ovarian cancer patients (Mantel-Cox log rank p value 0.0005). Median survival was 49 months for patients with high TGF-P2 methylation and 42 months for patients with low TGF-P2 methylation. Results are shown in Table 30 and Table 31.Table 30: Survival for pancreatic cancer patientsTable 31 : Survival for pancreatic cancer patientsDocket No. 018988-024WO1

[0354] Example 18. FIG. 18 shows results of a study of clinical outcomes in PDAC pancreatic cancer (KMPlotter). FIG. 18 shows that for PDAC pancreatic cancer patients with HDAC1 below median level, patients with low TGF-P2 expression achieved significantly and surprisingly increased overall survival (logrank P = 0.0018). In this study, overall survival of patients with HDAC1 below median surprisingly improved from 16 months to 38 months.

[0355] Thus, these results show that for PDAC pancreatic cancer patients in treatment with antisense agent OT-101 which always lowers TGF-P2 expression, reduced expression level of HDAC1 guides the OT-101 therapy to surprisingly increased overall survival. Thus, patients in the upper curve in FIG. 18 reflect a distinguished group capable of surprisingly increased overall survival.

[0356] For PDAC pancreatic cancer, FIG. 18 shows HD AC synergy with TGF-P2. Median survival reflected in FIG. 18 was surprisingly improved from 16 months to 38 months for PDAC pancreatic cancer patients in the distinguished group with HDAC1 below median level and low TGF-P2 expression. Results are shown in Table 32.Table 32: Survival for pancreatic cancer patients

[0357] Parameters for the study were as follows:

[0358] Restrictions of Tumor type: Pancreatic ductal adenocarcinoma.

[0359] Restrictions of Tumor subtype: all stages, all genders, all races, all grades, all Mutation burden, all Neoantigen load.Docket No. 018988-024WO1

[0360] Restrictions of cellular content: all Basophils, all B-cells, all CD4+ memory T-cells, all CD8+ T-cells, all Eosinophils, all Macrophages, all Mesenchymal stem cells, all Natural killer T-cells, all Regulatory T-cells, all Type 1 T-helper cells, all Type 2 T-helper cells.

[0361] Example 19 FIG. 19 shows results of a study of clinical outcomes in stomach cancer (KMPlotter). FIG. 19 shows that for stomach cancer patients with HDAC2 below median level, patients with low TGF-P2 expression achieved significantly and surprisingly increased overall survival (logrank P = 0.0044). Overall survival of patients with HDAC2 below median surprisingly improved from 19 months to 70 months.

[0362] Thus, these results show that for stomach cancer patients in treatment with antisense agent OT-101 which always lowers TGF-P2 expression, reduced expression level of HDAC2 guides the OT-101 therapy to surprisingly increased overall survival. Thus, patients in the upper curve in FIG. 19 reflect a highly distinguished group capable of surprisingly increased overall survival.

[0363] For stomach cancer, FIG. 19 shows HDAC synergy with TGF-P2. Median survival reflected in FIG. 19 was surprisingly improved from 19 months to 70 months for stomach cancer patients in the distinguished group with HDAC2 below median level and low TGF-P2 expression. Results are shown in Table 33.Table 33 : Survival for stomach cancer patients

[0364] Parameters for the study were as follows:Docket No. 018988-024WO1

[0365] Restrictions of Tumor type: Stomach adenocarcinoma.

[0366] Restrictions of Tumor subtype: all stages, all genders, all races, all grades, all Mutation burden, all Neoantigen load.

[0367] Restrictions of cellular content: all Basophils, all B-cells, all CD4+ memory T-cells, all CD8+ T-cells, all Eosinophils, all Macrophages, all Mesenchymal stem cells, all Natural killer T-cells, all Regulatory T-cells, all Type 1 T-helper cells, all Type 2 T-helper cells.

[0368] Example 20. FIG. 20 shows results of a study of clinical outcomes in ovarian cancer (KMPlotter). FIG. 20 shows that for ovarian cancer patients with HDAC1 below median level, patients with low TGF-P2 expression achieved significantly and surprisingly increased progression free survival (logrank P = 0.00057). Overall survival for patients with HDAC1 below median improved from 19 months to 27 months.

[0369] Thus, these results show that for ovarian cancer patients in treatment with antisense agent OT-101 which always lowers TGF-P2 expression, reduced expression level of HDAC1 guides the OT-101 therapy to surprisingly increased overall survival. Thus, patients in the upper curve in FIG. 20 reflect a highly distinguished group capable of surprisingly increased overall survival.

[0370] For ovarian cancer, FIG. 20 shows HDAC synergy with TGF-P2. Median survival reflected in FIG. 20 was surprisingly improved from 19 months to 27 months for stomach cancer patients in the distinguished group with HDAC1 below median level and low TGF-P2 expression. Results are shown in Table 34.Table 34: Survival for ovarian cancer patientsDocket No. 018988-024WO1

[0371] Parameters for the study were as follows:

[0372] Restrictions of Tumor type: Stomach adenocarcinoma.

[0373] Restrictions of Tumor subtype: all histology, all stages, all grades, all TP53 mutation, all debulking, all Chemotherapy, not checked, average CA125.

[0374] Example 21 A clinical trial confirmed that expression of TGF-P2 was suppressed by antisense agent OT-101 and further showed that overall survival in cancer patients was improved by administering antisense agent OT-101, especially for younger patients less than 60 years of age.

[0375] FIG. 21 shows results of clinical trial outcomes in pancreatic cancer (P001, Phase I / II OT-101 multicenter dose-escalation clinical study conducted in Germany in adult patients (n = 61), stage III or IV (AJCC standard) with advanced pancreatic cancer (n = 37), malignant melanoma (n = 19), and colorectal cancer (n = 5)). It was found that age was associated with increased survival for younger patients, as compared to older patients. FIG. 21 shows that age was associated with significantly improved survival for younger patients (Mantel-Cox log rank p value 0.0139). Median overall survival was 5 months for younger patients, which was more than double the 2 months found for older patients.

[0376] In P001, patients were treated with OT-101 by continuous intravenous (IV) infusion in escalating doses (40 mg / m2 / day up to 330 mg / m2 / day) of two treatment schedules (initial schedule: 7-days on, 7-days off (n = 17); modified schedule: 4-days on, 10-days off (n = 44); two cycles as core study and up to 10 cycles for expanded study). The dose of 140 mg / m2 / day was chosen based upon a trend for better tolerability as compared to higher doses for this schedule while also showing some disease stabilization during the escalation phase.

[0377] Results are shown in Table 35 and Table 36.Table 35: Survival for pancreatic cancer patientsDocket No. 018988-024WO1Table 36: Survival for pancreatic cancer patients

Claims

Docket No. 018988-024WO1WHAT IS CLAIMED IS:

1. A composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

2. A composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for use in the preparation of a medicament for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

3. A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering to the subject a therapeutically sufficient amount of a composition comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent; wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

4. The composition or method of any of claims 1-3, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

5. The composition or method of any of claims 1-3, wherein the low histone deacetylases are reduced expression of one or both of HD AC 1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

6. The composition or method of any of claims 1-3, wherein the subjects are less than 59 years of age.

7. The composition or method of any of claims 1-3, wherein the DNA alkylating agent is an SN1 or SN2 alkylating agent.

8. The composition or method of any of claims 1-3, wherein the DNA alkylating agent is procarbazine, dacarbazine, carbamazepine, temozolomide, streptozotocin, 1 -methyl- 1- nitrosourea, N-methyl-N’-nitro-N-nitrosoguanidine, methyl methanesulfonate, N,N-dimethyl-D- erythro-sphingosine, melphalan, melphalan flufenamide, busulfan, mechlorethamine,Docket No. 018988-024WO1 cyclophosphamide, ifosfamide, bendamustine, chlorambucil, carmustine, lomustine, altretamine, thiotepa, or a salt or ester form of any of the foregoing, or a combination thereof.

9. The composition or method of any of claims 1-3, wherein the DNA alkylating agent is carboplatin, cisplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin tetranitrate, or a salt or ester form of any of the foregoing, or a combination thereof.

10. The composition or method of any of claims 1-3, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

11. The composition or method of any of claims 1-3, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre-mRNA or mRNA and 18-21 nucleotides in length.

12. The composition or method of any of claims 1-3, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.

13. The composition or method of any of claims 1-3, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

14. The composition or method of any of claims 1-3, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-0Me ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

15. The composition or method of any of claims 1-3, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a tri antenarry N -actey 1 -gal actosamine .Docket No. 018988-024WO116. The composition or method of any of claims 1-3, wherein the composition comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

17. The composition or method of any of claims 1-3, wherein the composition is substantially free of excipients.

18. The composition or method of any of claims 1-3, wherein the composition is stable for at least 14 days in carrier at 37°C.

19. The composition or method of any of claims 1-3, wherein the composition is administered by infusion or injection.

20. The composition or method of any of claims 1-3, wherein the composition increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

21. A medical product comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

22. A medical product comprising an antisense agent for suppressing expression of TGF-P2 and a DNA alkylating agent in the preparation of a medicament for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

23. A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering to the subject a therapeutically sufficient amount of an antisense agent for suppressing expression of TGF-P2; and administering to the subject a DNA alkylating agent; wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

24. The medical product or method of any of claims 21-23, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.Docket No. 018988-024WO125. The medical product or method of any of claims 21-23, wherein the low histone deacetylases are reduced expression of one or both of HD AC 1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

26. The medical product or method of any of claims 21-23, wherein the subjects are less than 59 years of age.

27. The medical product or method of any of claims 21-23, wherein the antisense agent for suppressing expression of TGF-P2 and the DNA alkylating agent are administered concurrently, simultaneously, sequentially, or separately in time.

28. The medical product or method of any of claims 21-23, wherein the DNA alkylating agent is an SN1 or SN2 alkylating agent.

29. The medical product or method of any of claims 21-23, wherein the DNA alkylating agent is procarbazine, dacarbazine, carbamazepine, temozolomide, streptozotocin, 1-methyl-l- nitrosourea, N-methyl-N’-nitro-N-nitrosoguanidine, methyl methanesulfonate, N,N-dimethyl-D- erythro-sphingosine, melphalan, melphalan flufenamide, busulfan, mechlorethamine, cyclophosphamide, ifosfamide, bendamustine, chlorambucil, carmustine, lomustine, altretamine, thiotepa, or a salt or ester form of any of the foregoing, or a combination thereof.

30. The medical product or method of any of claims 21-23, wherein the DNA alkylating agent is carboplatin, cisplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin tetranitrate, or a salt or ester form of any of the foregoing, or a combination thereof.

31. The medical product or method of any of claims 21-23, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

32. The medical product or method of any of claims 21-23, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre-mRNA or mRNA and 18-21 nucleotides in length.Docket No. 018988-024WO133. The medical product or method of any of claims 21-23, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.

34. The medical product or method of any of claims 21-23, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

35. The medical product or method of any of claims 21-23, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-0Me ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

36. The medical product or method of any of claims 21-23, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a tri antenarry N -actey 1 -gal actosamine .

37. The medical product or method of any of claims 21-23, wherein the antisense agent and the DNA alkylating agent are singly formulated, and wherein the antisense agent formulation comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof, and wherein the DNA alkylating agent formulation comprises an oral or intravenous dosage form.

38. The medical product or method of any of claims 21-23, wherein the medical product or method increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

39. The medical product or method of any of claims 21-23, wherein the composition is combined with a standard of care treatment for the cancer.

40. A composition comprising an antisense agent for suppressing expression of TGF-P2 for treating or ameliorating the symptoms of cancer in a subject, wherein the subjects are selected who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression.Docket No. 018988-024WO141. A composition comprising an antisense agent for suppressing expression of TGF-P2 in the preparation of a medicament for treating or ameliorating the symptoms of cancer in subjects who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression.

42. A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: selecting subjects who have one or both of (a) low genomic DNA methylation and (b) high TGF-P2 expression; and administering a therapeutically sufficient amount of an agent for suppressing expression of TGF-P2 to the subjects.

43. The composition or method of any of claims 40-42, wherein the cancer is pancreatic cancer, ovarian cancer, stomach cancer, brain or spinal cancer, glioma, glioblastoma, or diffuse midline glioma (DMG).

44. The composition or method of any of claims 40-42, wherein the low genomic DNA methylation is reduced genomic DNA methylation below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

45. The composition or method of any of claims 40-42, wherein the subjects are less than 59 years of age.

46. The composition or method of any of claims 40-42, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript and 15-30 nucleotides in length.

47. The composition or method of any of claims 40-42, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 pre-RNA, pre-mRNA or mRNA and 18-21 nucleotides in length.

48. The composition or method of any of claims 40-42, wherein the antisense agent for suppressing expression of TGF-P2 comprises one or more TGF-P2-specific antisense oligonucleotides complementary to a TGF-P2 transcript as in Table 1.

49. The composition or method of any of claims 40-42, wherein the antisense agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.Docket No. 018988-024WO150. The composition or method of any of claims 40-42, wherein the antisense agent for suppressing expression of TGF-P2 comprises a sequence as in Table 1 and comprise one or more nucleotides chemically modified as a phosphorothioate internucleoside linkage, a methoxypropylphosphonate internucleoside linkage, an aminophosphoro linkage to a morpholino group, a 2’-0Me ribose group, a 2’ -MOE methoxy ethyl ribose group, a 2’ -4’ constrained methoxy ethyl bicyclic ribose group, a 2’ -4’ constrained ethyl bicyclic ribose group, an LNA ribose group, a 2’-F ribose group, or a 5-methylcytodine base.

51. The composition or method of any of claims 40-42, wherein the antisense agent for suppressing expression of TGF-P2 is conjugated to a polyethylene glycol, a lipid, or a tri antenarry N -actey 1 -gal actosamine .

52. The composition or method of any of claims 40-42, wherein the composition comprises a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.

53. The composition or method of any of claims 40-42, wherein the composition is substantially free of excipients.

54. The composition or method of any of claims 40-42, wherein the composition is administered by infusion or injection.

55. The composition or method of any of claims 40-42, wherein the composition increases survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

56. The composition or method of any of claims 40-42, wherein the composition or method is combined with a standard of care treatment for the cancer.

57. A method for collecting data, the method comprising: obtaining data relating to an individual subject or a group of subjects to generate a dataset comprising mRNA levels or protein levels of the subjects for TGF-P2 and one or both of HDAC1 and HDAC2.

58. The method of claim 57, comprising obtaining one or more clinical parameters from the subjects selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

59. The method of claim 57, wherein the subjects are less than 59 years of age.Docket No. 018988-024WO160. A method for diagnosing or prognosing pancreatic, stomach, or ovarian cancer in an individual subject, the method comprising: obtaining data for a control group of subjects to generate a control dataset comprising mRNA levels or protein levels of the subjects for TGF-P2 and one or both of HDAC1 and HDAC2, wherein the control group of subjects have previously been diagnosed with pancreatic, stomach, or ovarian cancer; obtaining data for a sample from the individual subject to generate an individual dataset comprising mRNA levels or protein levels of the individual subject for TGF-P2 and one or both of HD AC 1 and HDAC2; comparing the dataset of the individual subject to the dataset of the control group; and determining differences between the datasets of the individual subject and the control group, where the differences meet a threshold for indicating pancreatic, stomach, or ovarian cancer in the individual subject.

61. The method of claim 60, comprising obtaining a value for one or more clinical parameters for the subjects of the control group and the individual subject, the clinical parameters selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

62. The method of claim 60, comprising diagnosing or prognosing cancer disease progression in the subject.

63. The method of claim 60, comprising treating the subject for cancer by administering an anti -cancer drug.

64. A method for diagnosing or prognosing pancreatic, stomach, or ovarian cancer in an individual subject, the method comprising: obtaining data for control human mRNA levels or protein levels for TGF-P2 and one or both of HD AC 1 and HDAC2; obtaining data for an individual human subject comprising mRNA levels or protein levels for TGF-P2 and one or both of HDAC1 and HDAC2; comparing the data for the individual human subject to the control human mRNA levels or protein levels; and determining differences between the data for the individual human subject and the control human mRNA levels or protein levels exceeding a threshold for indicating pancreatic, stomach, or ovarian cancer in the individual subject.Docket No. 018988-024WO165. The method of claim 64, wherein the control human mRNA levels or protein levels are obtained from a control group of subjects, wherein the control group comprises: a group of subjects who do not have pancreatic, stomach, or ovarian cancer; a group of subjects who do not present any symptoms of pancreatic, stomach, or ovarian cancer; a monitored group of subjects who do not have pancreatic, stomach, or ovarian cancer at any time; a tested group of subjects who have a known risk of pancreatic, stomach, or ovarian cancer; a patient group of subjects who have been diagnosed with an early stage of pancreatic, stomach, or ovarian cancer; or a patient group of subjects who have been diagnosed with a late stage of pancreatic, stomach, or ovarian cancer; wherein any of the above control groups have been, or have not been treated for cancer.

66. The method of claim 64, comprising obtaining a value for one or more clinical parameters for the subjects of the control group and the individual human subject, the clinical parameters selected from age, sex, race / ethnicity, medical history, alcohol, chemical exposure, and smoking.

67. The method of claim 64, comprising diagnosing or prognosing pancreatic, stomach, or ovarian cancer disease, or pancreatic, stomach, or ovarian cancer disease progression in the subject.

68. The method of claim 64, comprising treating the individual human subject for pancreatic, stomach, or ovarian cancer by administering an anti-cancer drug.

69. A medical product kit for determining expression levels of TGF-P2 and one or both of HDAC1 and HDAC2 in a subject with a blood sample, a CSF sample, a fresh frozen sample, a snap frozen sample, an FFPE sample, or a biopsy sample, the medical product kit comprising reagents for specifically detecting the expression levels.

70. The medical product kit of claim 69 for use in diagnosing or prognosing pancreatic, stomach, or ovarian cancer.

71. A composition comprising an antisense agent for suppressing expression of TGF-P2 and a carrier for use in treating or ameliorating the symptoms of cancer in a subject in combinationDocket No. 018988-024WO1 with an HD AC inhibitor, wherein the subject has TGF-P2 expression above a median level of subjects with the same disease.

72. A method for treating or ameliorating the symptoms of cancer in a subject in need, the method comprising: administering a composition comprising an antisense agent for suppressing expression of TGF-P2 and a carrier to the subject; and administering an HD AC inhibitor to the subject; wherein the agents are singly-formulated and administered concurrently, simultaneously, sequentially, or separately in time; wherein the subject has TGF-P2 expression above a median level of subjects with the same disease.

73. The composition or method of any of claims 71-72, wherein the subjects are selected who have (a) high TGF-P2 expression and (b) low histone deacetylases.

74. The composition or method of any of claims 71-72, wherein the cancer is glioma, glioblastoma, diffuse midline glioma (DMG), brain or spinal cancer, pancreatic cancer, ovarian cancer, or stomach cancer.

75. The composition or method of claim 73, wherein the low histone deacetylases are reduced expression of one or both of HD AC 1 and HDAC2 below median of a control, and wherein the high TGF-P2 expression is TGF-P2 expression above median of a control.

76. The composition or method of any of claims 71-72, wherein the subjects are less than 59 years of age.

77. The composition or method of any of claims 71-72, wherein the HD AC inhibitor is vorinostat, valproic acid, belinostat, panobinostat, tucidinostat, or a salt or ester form of any of the foregoing, or a combination thereof.

78. The composition or method of any of claims 71-72, wherein the agent for suppressing expression of TGF-P2 comprises OT-101 C*G*G*C*A*T*G*T*C*T*A*T*T*T*T*G*T*A SEQ ID NO: 1.

79. The composition or method of any of claims 71-72, comprising a carrier of sterile water for injection, saline, isotonic saline, phosphate buffered saline, or a combination thereof.Docket No. 018988-024WO180. The composition or method of any of claims 71-72, wherein the agents or medicament are for infusion or injection, or are an oral dosage form.

81. The composition or method of any of claims 71-72, wherein the administration of the agent for suppressing expression of TGF-P2 comprises two or more cycles of 7-day or 4-day intravenous infusion, wherein successive cycles are separated by a 10-day treatment-free interval, and wherein the dosage is 50 to 330 mg / m2 / day.

82. The composition or method of any of claims 71-72, wherein the agents, use or method increases a survival rate of subjects at month 6, 12, 18, 24, 30, or 36.

83. The composition or method of any of claims 71-72, wherein the composition or method is combined with a standard of care treatment for cancer.

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