Enantiomers of azopodophyllotoxin derivative SU056

Abstract

The present invention also relates to a novel enantiomer of 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (SU056), as well as pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use in medical treatments, particularly in the treatment of cancer. TIFF2025523065000005.tif79128

Description

Technical Field

[0001] Reference to Related Applications This application claims priority under 35 U.S.C.§119(e) to U.S. Provisional Patent Application No. 63 / 388,537, filed on July 12, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] Field of the Invention The present invention relates to a novel levorotatory enantiomer (L-SU056) of 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one, and to its use in medical treatment, including in particular the treatment of cancer.

Background Art

[0003] Background of the Invention Y-box binding protein 1 (YB-1, YBX1) is a multifunctional cold shock protein that binds to DNA and RNA, which is associated with tumor progression and the emergence of treatment resistance (TR). It regulates DNA- and RNA-related cellular events, including mRNA transcription, splicing, packaging, stabilization, and translation (Lyabin et al., 2014, "YB-1 protein: functions and regulation", Wiley Interdiscip Rev RNA, 5, 95-110). mRNA stabilization is an important event for sustained expression of any gene, and YB-1 firmly stabilizes mRNA by protecting the 5' end so that the mRNA is not degraded (Evdokimova et al., 2001, "The major mRNA-associated protein YB-1 is a potent 5' cap-dependent mRNA stabilizer", EMBO J, 20, 5491-502). YB-1 was first reported by Didier et al. as a negative regulator of MHC class II molecules (Didier et al., 1988). The oncogenic role of YB-1 has been well characterized in many cancers, and an increase in its level has been found in a large number of cancer cases (Goodarzi et al., Cell 161, 790-802, 2015).YB-1 increases the stability of short-lived mRNAs for multiple oncogenic proteins associated with disease progression and treatment resistance, where the oncogenic proteins include the following: c-myc (Laird-Offringa et al., 1990, "Poly(A) tail shortening is the translation-dependent step in c-myc mRNA degradation", Mol Cell Biol, 10, 6132-40), c-fos (Blattner et al., 2000, "UV-Induced stabilization of c-fos and other short-lived mRNAs", Mol Cell Biol, 20, 3616-25), cyclin B1 (Maity et al., 2011, "Class III beta-tubulin (TUBB3): more than a biomarker in solid tumors?", Curr Mol Med, 11, 726-31), HIF1α (Goodarzi et al., 2015, "Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement", Cell, 161, 790-802), Snail (Evdokimova et al., 2009, "Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition", Cancer Cell, 15, 402-15), and MDR1 (Bargou et al., 1997).Gene knockdown studies have demonstrated that inhibition of YB-1 significantly suppresses proliferation and induces apoptosis in many cancer models, attesting to its essential role in disease progression (Evdokimova et al., 2009, El-Naggar et al., 2015, "Translational Activation of HIF1alpha by YB-1 Promotes Sarcoma Metastasis", Cancer Cell, 27, 682-97). YB-1 is involved in the development of treatment resistance (TR) through its role in activating proliferation, promoting cancer cell stemness, responding to growth factors, cytokines, and cellular stress, and promoting drug efflux by the P-glycoprotein, also known as ABCB1 (MDR1), an ATP-dependent efflux pump in the membrane (Bargou et al., 1997, "Nuclear localization and increased levels of transcription factor YB-1 in primary human breast cancers are associated with intrinsic MDR1 gene expression", Nat Med, 3, 447-50; Saupe et al., 2015, "Differential expression of the multidrug resistance 1 (MDR1) protein in prostate cancer cells is independent from anticancer drug treatment and Y box binding protein 1 (YB-1) activity", World J Urol, 33, 1481-6; and Mo et al., 2016, "Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT-YB1-MDR1 Signaling Pathway", Cancer Res, 76, 3057-66).YB-1 is also involved in the alternative splicing of CD44 exons through its association with A / C-rich regions (Stickeler et al., 2001, "The RNA binding protein YB-1 binds A / C-rich exon enhancers and stimulates splicing of the CD44 alternative exon v4", EMBO J, 20, 3821-30). The YB-1 gene is highly conserved and shows mutations in only approximately 1% of cancer patients, yet it is highly expressed in a wide range of cancers through another gene regulatory network.

[0004] Ovarian cancer (OC) accounts for only 3% of all cancer cases in women, yet it results in a disproportionate mortality rate (Dietl, 2014, "Revisiting the pathogenesis of ovarian cancer: the central role of the fallopian tube", Arch Gynecol Obstet, 289, 241-6; Jayson et al., 2014, "Ovarian cancer", Lancet, 384, 1376-88; Agarwal and Kaye, 2003, "Ovarian cancer: strategies for overcoming resistance to chemotherapy", Nat Rev Cancer, 3, 502-16). Surgical resection followed by chemotherapy is the main treatment strategy for OC patients. Platinum-based drugs and taxol-based drugs, as well as combinations thereof, are first-line treatments for the majority of OC patients (Seifter, 1997, "Cancer: Principles and Practice of Oncology", 5th Edition, Vincent T. DeVita, Jr., Samuel Hellman, Steven A. Rosenberg, eds. Philadelphia: Lippincott-Raven Publishers, 1997. 3125 pp., illus. ISBN 0-397-51573-4. JNCI: Journal of the National Cancer Institute, 89, 353-353). The majority of women are diagnosed with stage III+ OC and often experience TR and disease recurrence.BRCA1 / 2 mutations, MYC amplification, and upregulation of MDR1 (ABCB1 / P-gp) are the most widely known factors for TR in OC (Zeng et al., 2018, "Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12 / 13", Elife, 7; Christie and Bowtell, 2017, "Acquired chemotherapy resistance in ovarian cancer", Ann Oncol, 28, viii13-viii15; Sun et al., 2015, "Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: Analysis of the androgen receptor", Oncotarget, 6, 27065-82). Patient-based studies have shown that MYC amplification is associated with disease progression and TR in many lesions of high-grade epithelial OC (Jung et al., 2017, "A Myc Activity Signature Predicts Poor Clinical Outcomes in Myc-Associated Cancers", Cancer Res, 77, 971-981; and Jung et al., 2018, "Clinical Importance of Myc Family Oncogene Aberrations in Epithelial Ovarian Cancer", JNCI Cancer Spectrum, 2).The nuclear localization of YB-1 plays an important role in the regulation of MYC, MDR1, and CD44 (Kang et al., 2013, "Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer", J Natl Cancer Inst, 105, 1485-95; Sobocan et al., 2020, "The Communication Between the PI3K / AKT / mTOR Pathway and Y-box Binding Protein-1 in Gynecological Cancer", Cancers (Basel), 12). Analysis of high-grade serous ovarian cancer tumor samples has suggested that patients with higher YB-1 expression (median survival 48.5 months) had a shorter survival compared to patients with lower YB-1 expression (median survival 65 months) (Kang et al., 2013). Following primary treatment for OC, such as surgery and chemotherapy, maintenance therapy can be performed, which includes long-term use of agents such as paclitaxel as well as PARP inhibitors (olaparib, pazopanib, and niraparib), but unfortunately, the outcomes are still limited (Franzese et al., 2019, "PARP inhibitors in ovarian cancer", Cancer Treat Rev, 73, 1-9). It is strongly suggested from the literature over the past 30 years that YB-1 could be a potential target for treating ovarian cancer and also for treating other cancers, including those that have developed treatment resistance. Even after extensive investigation, no large-scale efforts have been made to develop small molecule inhibitors capable of directly inhibiting YB-1. Y-box binding protein 1 (YB-1) is encoded by the YBX1 gene, has been pointed out to change or regulate cellular signaling pathways, and can be considered as a molecular marker of cancer progression and as a target for cancer therapy.

[0005] Lasham et al. describe how "YB-1 regulates multiple proliferation pathways, overrides cell-cycle check points, promotes replicative immortality and genomic instability, may regulate angiogenesis, has a role in invasion and metastasis, and promotes inflammation" in their review article: "YB-1: oncoprotein, prognostic marker and therapeutic target?", Biochem. J. (2013) 449, 11-13. Lasham et al. further described cell lines in which apoptosis was induced or cell proliferation was inhibited by reducing YB-1, including melanoma, fibrosarcoma, liver cancer, lung cancer, bladder cancer, multiple myeloma, pediatric glioblastoma, breast cancer (ER negative), breast cancer (ER positive), prostate cancer, and colon cancer cell lines.

[0006] Sobocan et al. (Cancers, 2020, 12, 205) describe dual targeting of Y-box protein 1 (YB-1) with mTOR to improve inhibition of oncogenic activity in gynecological cancers, including ovarian, endometrial, fallopian tube, and cervical cancer.

[0007] The following paper describes the function of YBX2 in promoting the transcriptional activation of the gene of the transporter ABCB1, where ABCB1 is related to the transcriptional mechanism of how tumors acquire multidrug resistance during chemotherapy treatment in human malignant diseases including breast cancer, lung cancer, ovarian cancer, prostate cancer, colorectal cancer, and gastric cancer: "Oncogenic Y-box binding protein-1 as an effective therapeutic target in drug-resistant cancer", Kuwano et al., Cancer Science, 2019, 110:1536-1543.

[0008] The relationship between increased expression of YBX1 and melanoma has been discussed in the following paper: "The increased expression of Y box-binding protein 1 in melanoma stimulates proliferation and tumor invasion, antagonizes apoptosis and enhances chemoresistance", Schittek et al., Int. J. Cancer: 120, 2110-2118 (2007). The high expression of YB1 is also related to radiation resistance in colorectal cancer cells as discussed below: Kim et al., Mol. Cancer Ther., 30 Oct 2019, 19(2), 479-89.

[0009] WO 2019 / 178091 A1 (Malholtra et al., The Board of Trustees of the Leland Stanford Junior University) teaches novel N-hydroxyethyldidehydroazapodophyllotoxins as GBP1 inhibitors and methods for using them in overcoming treatment resistance in cancer. The disclosure includes the compound 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (SU056).

[0010] There is still a need for small molecule inhibitors of YB-1 for pharmaceutical use, particularly those useful in the treatment of platinum-resistant cancers. SUMMARY OF THE INVENTION

[0011] Provided is a composition comprising (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof, its cocrystal, its ester, its solvate, its hydrate, its isomer (including its optical isomer, its racemate, or other mixture thereof), its tautomer, its isotope, its polymorph, or a pharmaceutically acceptable prodrug thereof, wherein the composition substantially does not contain (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof, its cocrystal, its ester, its solvate, its hydrate, its isomer (including its optical isomer, its racemate, or other mixture thereof), its tautomer, its isotope, its polymorph, or a pharmaceutically acceptable prodrug thereof. TIFF2025523065000002.tif62134 BRIEF DESCRIPTION OF THE DRAWINGS

[0012]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 2

Mode for Carrying Out the Invention

[0013] Detailed Description of the Invention (R)-9-(3-Fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof, its cocrystal, its ester, its solvate, its hydrate, its isomers (including its optical isomers, its racemate, or other mixtures thereof), its tautomers, its isotopes, its polymorphs, or a pharmaceutically acceptable prodrug thereof, with a certain enantiomeric excess with respect to (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof, its cocrystal, its ester, its solvate, its hydrate, its isomers (including its optical isomers, its racemate, or other mixtures thereof), its tautomers, its isotopes, its polymorphs, or a pharmaceutically acceptable prodrug thereof, a composition is provided.

[0014] The composition herein may also be referred to as a composition comprising (D)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((D)-SU506) or a pharmaceutically acceptable salt thereof, its cocrystal, its ester, its solvate, its hydrate, its isomers (including its optical isomers, its racemate, or other mixtures thereof), its tautomers, its isotopes, its polymorphs, or a pharmaceutically acceptable prodrug thereof, with a certain enantiomeric excess with respect to (L)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((L)-SU506) or a pharmaceutically acceptable salt thereof, its cocrystal, its ester, its solvate, its hydrate, its isomers (including its optical isomers, its racemate, or other mixtures thereof), its tautomers, its isotopes, its polymorphs, or a pharmaceutically acceptable prodrug thereof.

[0015] For the sake of brevity, reference to a pharmaceutically acceptable salt of (S)-SU506 or a pharmaceutically acceptable salt of (R)-SU506 is understood to also include reference to a cocrystal, ester, solvate, hydrate, isomer (including its optical isomers, its racemate, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof of said enantiomer.

[0016] There is provided a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of an enantiomeric excess of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof, or of an enantiomeric excess of (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier or excipient.

[0017] The compositions herein can be used in a method of medical treatment. For each of the treatment methods or inhibition methods described herein, there is an aspect where use of the term "composition" is intended to mean a composition of an enantiomeric excess of (S)-SU506 or a pharmaceutically acceptable salt thereof (or other forms listed above) with respect to (R)-SU506 or a pharmaceutically acceptable salt thereof (or other forms listed above). For each method, there is also an aspect where use of the term "composition" is intended to mean a pharmaceutical composition of an enantiomeric excess of (S)-SU506 or other forms of (S)-SU506 listed above with respect to (R)-SU506 or other forms of (R)-SU506 listed above, and a pharmaceutically acceptable excipient or carrier.

[0018] Also provided is a method of inhibiting the activity of YB1 protein in a subject experiencing cancer expressing YB1 protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising an effective amount of (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof and a certain enantiomeric excess of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof.

[0019] Further provided is a method of sensitizing cancer cells expressing YB1 protein in a subject to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising an effective amount of (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof and a certain enantiomeric excess of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof.

[0020] In addition, a method for sensitizing cancer cells expressing YB1 protein in a subject to treatment with radiation is provided, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising an effective amount of (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof and an enantiomeric excess of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof.

[0021] The treatment methods and sensitization methods herein for a subject having cancer expressing YB1 protein include those for cancers selected from the group consisting of gynecological cancers (including ovarian cancer, endometrial cancer, fallopian tube cancer, and cervical cancer), breast cancer, lung cancer, prostate cancer, colorectal cancer, bladder cancer, melanoma, liver cancer, multiple myeloma, soft tissue sarcoma, osteosarcoma, Ewing sarcoma, glioblastoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, kidney cancer, renal cell cancer, osteosarcoma, pancreatic cancer, head and neck cancer, nasopharyngeal cancer, and gastric cancer.

[0022] It is understood that the pharmaceutically effective amount of the composition described herein may be administered simultaneously with an additional anticancer agent or radiation in a regimen. In other embodiments, the pharmaceutically effective amount of the composition described herein may be administered to a subject in need thereof at a dose or in a regimen, followed by administration of one or more specified anticancer agents and / or radiation therapy.

[0023] In some embodiments, the compositions described herein may be administered over a first period, for example, 1 to 7 days, followed by administration of one or more specified anti-cancer agents and / or radiation therapy to the subject in need thereof.

[0024] In further embodiments, the compositions described herein and one or more specified anti-cancer agents and / or radiation therapy may be administered to the subject in need thereof by repeating consecutive periods, for example, periods of 1 to 14 days each, where there may or may not be a refractory period between each pair of administrations during which no treatment is performed.

[0025] In other embodiments, the compositions described herein may be administered over a first period, for example, 1 to 7 days, and after the first period, a second period may follow during which the subject in need thereof is co-administered both the composition described herein and a pharmaceutically effective amount of one or more specified anti-cancer agents and / or a pharmaceutically effective dose of radiation therapy.

[0026] In another embodiment, cancer cells expressing the YB1 (YBX1) protein in a subject that is sensitive or made sensitive to the treatment described herein are selected from the group consisting of gynecological cancers (including ovarian cancer, endometrial cancer, fallopian tube cancer, and cervical cancer), leukemia, lymphoma, kidney cancer, bladder cancer, pancreatic cancer, head and neck cancer, breast cancer (including triple-negative, ER-negative, ER-positive breast cancer, and progesterone-positive), lung cancer, ovarian cancer, prostate cancer, colorectal cancer, gastric cancer, and cancers of the nervous system (including glioma).

[0027] Gynecological cancer A method of treating a gynecological cancer in a subject expressing the YB1 (YBX1) protein is provided, the method comprising administering a pharmaceutically effective amount of the composition described herein to the subject in need thereof.

[0028] Also provided is a method of treating gynecological cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein and a pharmaceutically effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the mTOR inhibitor is selected from the group consisting of sirolimus, everolimus, deforolimus, and temsirolimus.

[0029] Also provided is a method of enhancing the effect of an anti-cancer agent in a subject experiencing gynecological cancer expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein. In some embodiments, treating with the composition described herein renders gynecological cancer cells expressing the YB1 (YBX1) protein in the subject sensitive to anti-cancer agent treatment.

[0030] In some embodiments, the anti-cancer agent used to treat gynecological cancer is an inhibitor or antagonist of phosphoinositide 3-kinase (PI3K) / protein kinase B (Akt).

[0031] In some embodiments, the gynecological cancer to be treated that expresses the YB1 (YBX1) protein is ovarian cancer. In other embodiments, the gynecological cancer to be treated is endometrial cancer. In still other embodiments, the gynecological cancer to be treated is cervical cancer.

[0032] Thus also provided is a method of treating ovarian cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, in the methods of treating gynecological cancers that express the YB1 (YBX1) protein discussed herein, the taxane compounds used are selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel.

[0034] For each method of sensitizing cancer cells expressing the YB1 (YBX1) protein in a subject to treatment with an anti-cancer agent and / or radiation, or for each method of inhibiting the activity of the YB1 protein in a subject experiencing cancer, there exists a corresponding method having: a first step of detecting the presence or absence of the YB1 (YBX1) protein expressed in a sample of cancer cells, and, when it is determined that the YB1 (YBX1) protein is present in the sample cells, treating the subject experiencing the cancer, for each such method, with a pharmaceutically effective amount of the composition described herein and one or more optional other agents specified by a particular method.

[0035] Also, as a non-limiting example, a method of treating ovarian cancer that expresses the YB1 (YBX1) protein in a subject is provided, the method comprising the steps of: (a) determining the presence or absence of the YB1 protein expressed in an ovarian cancer tumor sample taken from a subject in need thereof; and (b) when it is determined that the YB1 protein expressed in the ovarian cancer tumor sample is present, administering to the subject in need thereof: (i) a pharmaceutically effective amount of the composition described herein; and (ii) a pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof.

[0036] Thus also, a method of treating fallopian tube cancer (fallopian tube carcinoma) that expresses the YB1 (YBX1) protein in a subject is provided, the method comprising the step of administering to the subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof.

[0037] Thus, there is also provided a method for treating fallopian tube cancer (fallopian tube carcinoma) expressing YB1 (YBX1) protein in a subject, the method comprising the step of administering the following to a subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; (b) A pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof; and (c) A pharmaceutically effective amount of carboplatin or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the taxane compound in the method for treating fallopian tube cancer is selected from the group consisting of paclitaxel, albumin-bound paclitaxel, docetaxel, and cabazitaxel.

[0039] Prostate cancer There is also provided a method for treating prostate cancer expressing YB1 (YBX1) protein in a subject, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0040] Furthermore, there is provided a method for inhibiting the metastasis of prostate cancer expressing YB1 (YBX1) protein in a subject, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0041] In addition, there is provided a method for sensitizing prostate cancer expressing YB1 (YBX1) protein in a subject to treatment with an anti-cancer agent, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0042] In some embodiments, administering the compositions described herein renders prostate cancer expressing the YB1 (YBX1) protein in a subject sensitive to treatment with a taxane anti-cancer agent. In some embodiments, the taxane anti-cancer agent is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or pharmaceutically acceptable salts thereof.

[0043] Thus also provided is a method of treating prostate cancer expressing the YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of a taxane compound selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or pharmaceutically acceptable salts thereof.

[0044] In some embodiments, administering the compositions described herein renders prostate cancer expressing the YB1 (YBX1) protein in a subject sensitive to treatment with an anti-cancer agent that is an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from the group consisting of apalutamide, enzalutamide, darolutamide, and abiraterone acetate.

[0045] Thus also provided is a method of treating prostate cancer expressing the YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of an androgen receptor inhibitory compound selected from the group consisting of apalutamide, enzalutamide, darolutamide, and abiraterone acetate, or pharmaceutically acceptable salts thereof.

[0046] In some embodiments, apalutamide is administered to a subject in need thereof at a daily dosage of about 100 mg to about 300 mg. In some embodiments, apalutamide is administered to a subject in need thereof at a daily dosage of about 200 mg to about 300 mg. In some embodiments, apalutamide is administered at a dosage of about 240 mg per day.

[0047] In some embodiments, the anti-cancer agent is a luteinizing hormone-releasing hormone (LHRH) agonist. In some embodiments, the LHRH agonist is selected from the group consisting of leuprolide / leuprorelin, goserelin, triptorelin, buserelin, and histrelin.

[0048] Thus also provided is a method of treating prostate cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of a luteinizing hormone-releasing hormone (LHRH) agonist compound selected from the group consisting of leuprolide / leuprorelin, goserelin, triptorelin, buserelin, and histrelin, or a pharmaceutically acceptable salt thereof.

[0049] In other embodiments, the anti-cancer agent is a luteinizing hormone-releasing hormone (LHRH) antagonist. In some embodiments, the LHRH antagonist is degarelix.

[0050] Thus also provided is a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of degarelix or a pharmaceutically acceptable salt thereof.

[0051] In other embodiments, the anti-cancer agent is an anti-androgen agent. In some embodiments, the anti-androgen agent is selected from the group consisting of flutamide, bicalutamide, and nilutamide.

[0052] Thus, also provided is a method of treating prostate cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of an anti-androgen compound selected from the group consisting of flutamide, bicalutamide, and nilutamide, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments related to the methods herein for treating prostate cancer and / or inhibiting metastasis of prostate cancer, the prostate cancer is androgen-independent prostate cancer. In other embodiments, the prostate cancer is castration-sensitive prostate cancer. In other embodiments, the prostate cancer is castration-sensitive prostate cancer having distant metastases. In additional embodiments, the prostate cancer to be treated expressing YB1 (YBX1) protein is castration-resistant prostate cancer without distant metastases. In other embodiments, the prostate cancer is hormone-refractory prostate cancer (HRPC).

[0054] Melanoma Also provided is a method of treating melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0055] Further provided is a method of inhibiting metastasis of melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0056] In addition, a method for sensitizing melanoma cells expressing YB1 (YBX1) protein in a subject to treatment with an anti-cancer agent is provided, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0057] Thus also provided is a method of treating melanoma in a subject expressing YB1 (YBX1) protein, the method comprising administering to the subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of a PD-1 inhibitor selected from the group consisting of pembrolizumab and nivolumab, or a pharmaceutically acceptable salt thereof.

[0058] Further provided is a method of treating melanoma in a subject expressing YB1 (YBX1) protein, the method comprising administering to the subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of atezolizumab or a pharmaceutically acceptable salt thereof.

[0059] Further provided is a method of treating melanoma in a subject expressing YB1 (YBX1) protein, the method comprising administering to the subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; (b) a pharmaceutically effective amount of atezolizumab or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically effective amount of a third agent selected from the group consisting of cobimetinib and vemurafenib, or a pharmaceutically acceptable salt thereof.

[0060] Also provided is a method of treating melanoma in a subject expressing YB1 (YBX1) protein, the method comprising administering to the subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of a CTLA-4 inhibitor (e.g., ipilimumab).

[0061] Also provided is a method of treating melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of interleukin-2 (IL-2).

[0062] Cisplatin resistance Expression or overexpression of YB-1 is also associated with resistance to cisplatin treatment in some cancers, including breast cancer, bladder cancer, and ovarian cancer.

[0063] In some embodiments, the breast cancer to be treated is refractory to endocrine therapies, such as selective estrogen receptor modulators (SERMs) including tamoxifen and toremifene. In some embodiments, the breast cancer is refractory to selective estrogen receptor degraders (SERDs), such as fulvestrant and elacestrant. In other embodiments, the breast cancer to be treated is refractory to aromatase inhibitors, such as letrozole, anastrozole, exemestane, and testolactone.

[0064] Provided herein is a method of sensitizing a cancer expressing YB1 (YBX1) protein in a subject to treatment with cisplatin, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0065] Provided herein is a method of sensitizing a cancer expressing YB1 (YBX1) protein in a subject to treatment with a taxane compound, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0066] Breast cancer Also provided is a method of treating breast cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0067] Furthermore, provided is a method of inhibiting metastasis of breast cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0068] In addition, provided is a method of sensitizing breast cancer cells expressing the YB1 (YBX1) protein in a subject to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein. In some embodiments, the method sensitizes breast cancer cells expressing YB1 (YBX1) in a subject in need thereof to treatment with one or more agents selected from the following group: anthracyclines (e.g., doxorubicin, pegylated liposomal doxorubicin, and epirubicin), taxane compounds (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel, and cabazitaxel), 5-fluorouracil, capecitabine, cyclophosphamide, vinorelbine, gemcitabine, ixabepilone, eribulin, and platinum-based agents (e.g., carboplatin and cisplatin). In other embodiments, the method sensitizes breast cancer cells expressing YB1 (YBX1) to treatment with radiation therapy.

[0069] One embodiment provides a method of treating breast cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, docetaxel, 5-fluorouracil, capecitabine, cyclophosphamide, and carboplatin, or pharmaceutically acceptable salts thereof.

[0070] Another aspect provides a method for treating breast cancer expressing the YB1 (YBX1) protein in a subject, the method comprising administering the following to a subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of paclitaxel, albumin-bound paclitaxel, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, and eribulin, or pharmaceutically acceptable salts thereof.

[0071] Colorectal cancer Also provided is a method for treating colorectal cancer expressing the YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0072] Furthermore, provided is a method for inhibiting metastasis of colorectal cancer expressing the YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0073] In addition, provided is a method for making colorectal cancer cells expressing the YB1 (YBX1) protein in a subject sensitive to treatment with an anticancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0074] Also provided is a method for treating colorectal cancer expressing the YB1 (YBX1) protein in a subject, the method comprising the step of administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of 5-fluorouracil, capecitabine, irinotecan, oxaliplatin, and trifluridine / tipiracil, or a pharmaceutically acceptable salt thereof.

[0075] For each of the treatment methods herein that utilize the combination of trifluridine and tipiracil (trifluridine + tipiracil), the combination of the agents may include using the following individual dosages in various embodiments: (a) about 10 mg to about 20 mg of trifluridine and about 3 mg to about 10 mg of tipiracil; (b) about 12 mg to about 18 mg of trifluridine and about 4 mg to about 8 mg of tipiracil; (c) about 14 mg to about 16 mg of trifluridine and about 5 mg to about 7 mg of tipiracil; (d) about 10 mg to about 30 mg of trifluridine and about 5 mg to about 10 mg of tipiracil; and (e) about 15 mg to about 25 mg of trifluridine and about 6 mg to about 9 mg of tipiracil. In some embodiments, the daily dosage of the two agents includes about 60 mg to about 80 mg of trifluridine and about 20 mg to about 40 mg of tipiracil. In some embodiments, the daily dosage of the two agents includes about 65 mg to about 75 mg of trifluridine and about 25 mg to about 35 mg of tipiracil. In some embodiments, the daily dosage is defined as two administrations per day of about 30 mg to about 40 mg of trifluridine and about 12 mg to about 16 mg of trifluridine.

[0076] Bladder cancer Also provided is a method for treating bladder cancer expressing the YB1 (YBX1) protein in a subject, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0077] Furthermore, a method for inhibiting the metastasis of bladder cancer expressing YB1 (YBX1) protein in a subject is provided, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0078] In addition, a method for making bladder cancer cells expressing YB1 (YBX1) protein in a subject sensitive to treatment with an anticancer agent is provided, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0079] A method for treating bladder cancer expressing YB1 (YBX1) protein in a subject is provided, the method comprising administering to the subject in need thereof the following: (d) a pharmaceutically effective amount of the composition described herein; (e) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of cisplatin, cisplatin plus 5-fluorouracil, and mitomycin in combination with 5-fluorouracil, or a pharmaceutically acceptable salt thereof; (f) a therapeutically effective dose of radiation.

[0080] Also, a method for treating bladder cancer expressing YB1 (YBX1) protein in a subject is provided, the method comprising administering to the subject in need thereof the following: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of an anticancer agent selected from the following group: (i) gemcitabine and cisplatin; (ii) dose-dense methotrexate, vinblastine, doxorubicin (adriamycin), and cisplatin (DDMVAC); (iii) cisplatin, methotrexate, and vinblastine (CMV); and (iv) gemcitabine and paclitaxel.

[0081] Also provided is a method for treating bladder cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; (b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of docetaxel, paclitaxel, doxorubicin, methotrexate, ifosfamide, and pemetrexed, or a pharmaceutically acceptable salt thereof.

[0082] Liver cancer Also provided is a method for treating liver cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0083] Furthermore, provided is a method for inhibiting the metastasis of liver cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0084] In addition, provided is a method for making liver cancer cells expressing the YB1 (YBX1) protein in a subject sensitive to treatment with an anticancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0085] Thus also provided is a method for treating liver cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of gemcitabine, oxaliplatin, cisplatin, doxorubicin, 5-fluorouracil, capecitabine, and mitoxantrone, or a pharmaceutically acceptable salt thereof.

[0086] Lung cancer Also provided is a method for treating small cell lung cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0087] Furthermore, provided is a method for inhibiting metastasis of small cell lung cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0088] In addition, provided is a method for sensitizing small cell lung cancer cells expressing the YB1 (YBX1) protein in a subject to treatment with an anticancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0089] Thus also provided is a method for treating small cell lung cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof the following: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of cisplatin and etoposide, carboplatin and etoposide, and irinotecan, and carboplatin and irinotecan, or a pharmaceutically acceptable salt thereof.

[0090] Also provided is a method for treating non-small cell lung cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0091] Furthermore, provided is a method for inhibiting metastasis of non-small cell lung cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0092] In addition, provided is a method for sensitizing non-small cell lung cancer cells expressing YB1 (YBX1) protein in a subject to treatment with an anti-cancer agent, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0093] Thus also provided is a method for treating non-small cell lung cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anti-cancer agents selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed, or pharmaceutically acceptable salts thereof.

[0094] Multiple myeloma Also provided is a method for treating multiple myeloma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0095] Furthermore, provided is a method for inhibiting metastasis of multiple myeloma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0096] In addition, provided is a method for sensitizing multiple myeloma cells expressing YB1 (YBX1) protein in a subject to treatment with an anti-cancer agent, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0097] Also provided is a method of treating multiple myeloma expressing the YB1 (YBX1) protein in a subject, the method comprising the step of administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of an anti-cancer agent selected from the group consisting of melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, liposomal doxorubicin, and bendamustine, or a pharmaceutically acceptable salt thereof.

[0098] Soft tissue sarcoma Also provided herein is a method of treating soft tissue sarcoma expressing the YB1 (YBX1) protein, which soft tissue sarcomas include angiosarcoma, dermatofibrosarcoma protuberans, epitheloid sarcoma, gastrointestinal stromal tumor (GIST), Kaposi's sarcoma, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, rhabdomyosarcoma, solitary fibrous tumor, synovial sarcoma, and undifferentiated pleomorphic sarcoma.

[0099] Also provided is a method of treating a soft tissue sarcoma expressing the YB1 (YBX1) protein in a subject, such as a fibrosarcoma expressing the YB1 (YBX1) protein, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0100] Further provided is a method of inhibiting a soft tissue sarcoma expressing the YB1 (YBX1) protein in a subject, such as a fibrosarcoma expressing the YB1 (YBX1) protein, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0101] In addition, provided is a method for sensitizing soft tissue sarcoma cells expressing the YB1 (YBX1) protein in a subject, for example, fibrosarcoma cells expressing the YB1 (YBX1) protein, to treatment with an anticancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0102] Thus also provided is a method of treating a soft tissue sarcoma expressing the YB1 (YBX1) protein in a subject, for example, a fibrosarcoma expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of ifosfamide, doxorubicin, dacarbazine (DTIC), epirubicin, temozolomide, docetaxel, gemcitabine, vinorelbine, trabectedin, and eribulin, or pharmaceutically acceptable salts thereof.

[0103] In some embodiments, when the anticancer agent ifosfamide is used, the agent mesna is also administered to protect the bladder from the toxic effects of ifosfamide. In other embodiments, the anticancer agent is a combination of mesna, adriamycin [doxorubicin], ifosfamide, and dacarbazine, which may also be referred to by the acronym MAID. In other embodiments, the anticancer agent is a combination of adriamycin [doxorubicin], ifosfamide, and mesna, which may also be referred to by the acronym AIM. In some embodiments of the method of treating a soft tissue sarcoma herein, one or more anticancer agents are administered to a subject in need thereof using isolated limb perfusion.

[0104] Osteosarcoma : Also provided is a method for treating osteosarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0105] Furthermore, provided is a method for inhibiting osteosarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0106] In addition, provided is a method for sensitizing osteosarcoma cells expressing YB1 (YBX1) protein in a subject to treatment with an anticancer agent, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0107] Thus also provided is a method for treating osteosarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof the following: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of methotrexate, doxorubicin, cisplatin, carboplatin, ifosfamide, cyclophosphamide, etoposide, and gemcitabine, or pharmaceutically acceptable salts thereof.

[0108] In some embodiments of the method for treating osteosarcoma expressing the above-mentioned YB1 (YBX1) protein, the anticancer agent is a combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP regimen). In other embodiments, a combination of doxorubicin and cisplatin is administered. In other embodiments, a combination of ifosfamide and etoposide is used. In yet other embodiments, a combination of ifosfamide and epirubicin with either cisplatin or carboplatin is administered.

[0109] Ewing sarcoma Also provided is a method for treating Ewing's sarcoma expressing the YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0110] Furthermore, a method for inhibiting Ewing's sarcoma expressing the YB1 (YBX1) protein in a subject is provided, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0111] In addition, a method for sensitizing Ewing's sarcoma cells expressing the YB1 (YBX1) protein in a subject to treatment with an anticancer agent is provided, the method comprising administering to the subject in need thereof the composition described herein.

[0112] Thus also provided is a method for treating Ewing's sarcoma expressing the YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof the following: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of cyclophosphamide, doxorubicin, etoposide, ifosfamide, and vincristine, or pharmaceutically acceptable salts thereof.

[0113] In some embodiments of the methods for treating Ewing's sarcoma expressing the above-described YB1 (YBX1) protein, the anticancer agents are a combination of vincristine, doxorubicin, and cyclophosphamide that is repeated alternately with a combination of ifosfamide and etoposide, and this regimen is referred to as VDC / IE.

[0114] Stomach cancer Also provided is a method of treating gastric cancer (stomach cancer) in a subject expressing the YB1 (YBX1) protein, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0115] Furthermore, provided is a method of inhibiting gastric cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0116] In addition, provided is a method of sensitizing gastric cancer cells expressing the YB1 (YBX1) protein in a subject to treatment with an anticancer agent, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0117] Thus also provided is a method of treating gastric cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to the subject in need thereof the following: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of 5-fluorouracil, capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, irinotecan, oxaliplatin, paclitaxel, and trifluridine + tipracil (LONSURF (registered trademark)), or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments of methods of treating gastric cancer expressing the aforementioned YB1 (YBX1) protein, the anticancer agent is a combination of epirubicin, cisplatin, and 5-fluorouracil, which may also be referred to by the acronym ECF. In other embodiments, it is a combination of docetaxel or paclitaxel with either 5-FU or capecitabine, which may also be combined with radiation. In another embodiment, cisplatin is administered with either 5-FU or capecitabine, which may also be combined with radiation. In a further embodiment, paclitaxel and carboplatin are administered, which may also be combined with radiation. In other embodiments, a combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) is administered. In other cases, irinotecan is administered with cisplatin, with 5-fluorouracil, or with capecitabine. In still other cases, oxaliplatin is administered with 5-fluorouracil or with capecitabine. In yet other cases, trifluridine + tipiracil (LONSURF®) is administered.

[0119] Glioblastoma Also provided is a method of treating glioblastoma multiforme (GBM or glioblastoma) expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0120] Further provided is a method of inhibiting glioblastoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0121] In addition, a method is provided for sensitizing glioblastoma cells expressing the YB1 (YBX1) protein in a subject to treatment with an anticancer agent, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0122] Thus also provided is a method of treating glioblastoma in a subject expressing the YB1 (YBX1) protein, the method comprising administering to the subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of temozolomide, bevacizumab, romidepsin, carmustine, fluzoparil, pembrolizumab, nivolumab, ipilimumab, anlotinib, glasdegib, and bavituximab, or pharmaceutically acceptable salts thereof.

[0123] In some embodiments, the glioblastoma in the methods described above is a pediatric glioblastoma expressing the YB1 (YBX1) protein. In some embodiments, the glioblastoma is a primary glioblastoma expressing the YB1 (YBX1) protein. In other cases, the glioblastoma is a secondary glioblastoma expressing the YB1 (YBX1) protein.

[0124] Head and neck cancer References herein to "head and neck cancer" refer to any of the cancers below: oral cavity, larynx (pharynx including nasopharynx, oropharynx, and hypopharynx), larynx, paranasal sinuses, nasal cavity, and salivary glands. Head and neck cancers include hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, cervical squamous cell carcinoma with distant metastasis, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, and salivary gland cancer. For each of the methods of treating head and neck cancer described herein, it is understood that corresponding methods for each of the head and neck cancers listed in this paragraph are also disclosed.

[0125] Also provided is a method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0126] Furthermore, a method of inhibiting metastasis of head and neck cancer in a subject expressing the YB1 (YBX1) protein is provided, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0127] In addition, a method of sensitizing head and neck cancer expressing the YB1 (YBX1) protein in a subject to treatment with an anti-cancer agent is provided, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0128] In some embodiments related to the treatment of head and neck cancer expressing YB1 (YBX1), the anti-cancer agent used to treat the subject is radiotherapy. In some embodiments, the radiation utilized is external beam radiotherapy. In some embodiments, the treatment comprises administering to a subject in need thereof a pharmaceutically effective amount of one or more EGFR inhibitors. Other embodiments relate to administering to a subject in need thereof a pharmaceutically effective amount of larotrectinib (Vitrakvi) and / or larotrectinib, respectively.

[0129] Other methods of treating head and neck cancer include using immunotherapy, which can include, for example, administering to a subject in need thereof a pharmaceutically effective amount of pembrolizumab and / or nivolumab.

[0130] A method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein is provided, the method comprising administering to a subject in need thereof the following: (a) a pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of an anti-cancer agent selected from the group consisting of paclitaxel, docetaxel, cisplatin, carboplatin, 5-fluorouracil, methotrexate, and capecitabine, or a pharmaceutically acceptable salt thereof.

[0131] Thus, there is also provided a method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of a taxane compound selected from the group consisting of paclitaxel and docetaxel, or a pharmaceutically acceptable salt thereof.

[0132] There is also provided a method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, cisplatin is administered to a subject in need thereof at a dose of about 20 mg / m 2 ~ about 100 mg / m 2 delivered 3 times every 3 weeks.

[0134] There is also provided a method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of carboplatin or a pharmaceutically acceptable salt thereof; and (c) A pharmaceutically effective amount of an agent selected from the group consisting of 5-fluorouracil (5FU) and cetuximab.

[0135] Also provided is a method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically effective amount of an agent selected from the group consisting of 5-fluorouracil (5FU) and cetuximab.

[0136] Also provided is a method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically effective amount of paclitaxel or a pharmaceutically acceptable salt thereof.

[0137] Also provided is a method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of carboplatin or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically effective amount of paclitaxel or a pharmaceutically acceptable salt thereof.

[0138] Also provided is a method of treating head and neck cancer in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of hydroxyurea or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically effective amount of an agent selected from the group consisting of 5-fluorouracil (5FU) and cetuximab.

[0139] Furthermore, there is provided a method for treating nasopharyngeal cancer in a subject expressing YB1 (YBX1) protein, the method comprising the step of administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of hydroxyurea or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically effective amount of an agent selected from the group consisting of carboplatin, doxorubicin, epirubicin, paclitaxel, docetaxel, gemcitabine, bleomycin, and methotrexate.

[0140] Pancreatic cancer There is provided a method for treating pancreatic cancer in a subject expressing YB1 (YBX1) protein, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0141] Furthermore, there is provided a method for inhibiting metastasis of pancreatic cancer in a subject expressing YB1 (YBX1) protein, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0142] In addition, there is provided a method for making pancreatic cancer in a subject expressing YB1 (YBX1) protein sensitive to treatment with an anticancer agent, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0143] There is provided a method for treating pancreatic cancer in a subject expressing YB1 (YBX1) protein, the method comprising the step of administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of gemcitabine, 5-fluorouracil, oxaliplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, capecitabine, cisplatin, and irinotecan, or pharmaceutically acceptable salts thereof.

[0144] Nerve cancer The compositions described herein may also be used to treat nerve cancers (brain and spinal cord cancers) and / or to render the nerve cancers sensitive to treatment. The nerve cancers include medulloblastoma, glioblastoma multiforme (GBM), astrocytoma (anaplastic astrocytoma and pilocytic astrocytoma), ependymoma, and oligodendroglioma. For each of the following methods for treating nerve cancers or rendering nerve cancers sensitive to treatment described herein, it is understood that individual methods for each of the types of nerve cancers listed in this paragraph are included.

[0145] A method for treating a nerve cancer expressing the YB1 (YBX1) protein in a subject is provided, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0146] Furthermore, a method for inhibiting metastasis of a nerve cancer expressing the YB1 (YBX1) protein in a subject is provided, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0147] In addition, a method for rendering a nerve cancer expressing the YB1 (YBX1) protein in a subject sensitive to treatment with an anticancer agent is provided, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0148] A method for treating a cancer of a nerve expressing the YB1 (YBX1) protein in a subject is provided, the method comprising the step of administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of carboplatin, carmustine (BCNU), cisplatin, irinotecan, cyclophosphamide, etoposide, lomustine, methotrexate, procarbazine, temozolomide, and vincristine, or pharmaceutically acceptable salts thereof.

[0149] In some embodiments, the pharmaceutically effective amount of carmustine administered to a subject in need thereof is in the form of a wafer or implant of carmustine, which is, for example, in the form of the GLIADEL® wafer (carmustine implant) product commercially available from Arbor Pharmaceuticals, LLC.

[0150] Leukemia The method of the present invention also includes a method for treating leukemia, wherein the leukemia cells express the YB-1 protein, and leukemia includes acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (or acute lymphocytic leukemia) (ALL), and chronic lymphocytic leukemia (CLL). For each method described herein for treating leukemia or rendering leukemia sensitive to treatment, it is understood that each corresponding method is to be construed as for each of the leukemias mentioned (AML, CML, ALL, and CLL).

[0151] In addition, a method is provided for rendering leukemia cells expressing the YB1 (YBX1) protein in a subject sensitive to treatment with an anticancer agent, the method comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein. In some embodiments, the anticancer agent used to treat the subject is radiation therapy.

[0152] Also provided is a method for treating acute myeloid leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of an anthracycline agent selected from the group consisting of daunorubicin and idarubicin, or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically effective amount of cytarabine or a pharmaceutically acceptable salt thereof.

[0153] Also provided is a method for treating acute myeloid leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of cladribine (2-CdA), fludarabine, mitoxantrone, etoposide, 6-thioguanine, hydroxyurea, prednisone, dexamethasone, methotrexate, 6-mercaptopurine, azacitidine, and decitabine, or a pharmaceutically acceptable salt thereof.

[0154] Also provided is a method for treating chronic myeloid leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of hydroxyurea, cytarabine (Ara-C), busulfan, cyclophosphamide (CYTOXAN®), and vincristine (ONCOVIN®), or a pharmaceutically acceptable salt thereof.

[0155] Also provided is a method for treating chronic myeloid leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents that are tyrosine kinase inhibitors selected from the group consisting of imatinib (GLEEVEC®), dasatinib (SPRYCEL®), nilotinib (TASIGNA®), bosutinib (BOSULIF®), ponatinib (ICLUSIG®), and asciminib (SCEMBLIX®), or pharmaceutically acceptable salts thereof.

[0156] Also provided is a method for treating chronic myeloid leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of interferon-α or a pharmaceutically acceptable salt thereof.

[0157] Also provided is a method for treating acute lymphoblastic leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of vincristine, dexamethasone, imatinib, prednisone, doxorubicin, and daunorubicin, or pharmaceutically acceptable salts thereof.

[0158] Also provided is a method for treating acute lymphoblastic leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of one or more anti-cancer agents selected from the group consisting of methotrexate, 6-mercaptopurine, vincristine, prednisone, and imatinib, or pharmaceutically acceptable salts thereof.

[0159] Also provided is a method for treating acute lymphoblastic leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of one or more anti-cancer agents selected from the group consisting of vincristine, dexamethasone, prednisone, doxorubicin, and daunorubicin, or pharmaceutically acceptable salts thereof.

[0160] Also provided is a method for treating acute lymphoblastic leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of one or more anti-cancer agents selected from the group consisting of methotrexate, 6-mercaptopurine (6-MP), vincristine, prednisone, and imatinib, or pharmaceutically acceptable salts thereof.

[0161] Also provided is a method for treating chronic lymphocytic leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) A pharmaceutically effective amount of the composition described herein; and (b) A pharmaceutically effective amount of one or more anti-cancer agents selected from the group consisting of ibrutinib, acalabrutinib, idelalisib, and duvelisib, or pharmaceutically acceptable salts thereof.

[0162] Also provided is a method for treating chronic lymphocytic leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (b) a pharmaceutically effective amount of venetoclax or a pharmaceutically acceptable salt thereof.

[0163] Also provided is a method for treating chronic lymphocytic leukemia in a subject expressing the YB1 (YBX1) protein, the method comprising administering to a subject in need thereof: (a) a pharmaceutically effective amount of the composition described herein; and (c) a pharmaceutically effective amount of one or more anti-cancer agents selected from the group consisting of rituximab, ofatumumab, and obinutuzumab, or pharmaceutically acceptable salts thereof.

[0164] Definitions The terms "YB1" and "YBX1" refer to Y-box binding protein 1, which is a protein encoded by the YBX1 gene in humans and is also known as Y-box transcription factor or nuclease-sensitive element-binding protein 1.

[0165] In some embodiments, the "subject in need thereof" in connection with the treatment methods herein refers to a patient from whom a tumor sample, such as a tumor biopsy, has been taken and in which the presence of the expressed YBX1 protein has been identified, for example, by immunohistochemical techniques or Western blotting techniques known in the art.

[0166] The terms "effective amount", "therapeutically effective amount", or "pharmaceutically effective amount" refer to an amount sufficient to effect such treatment when administered to a subject in need of treatment (e.g., a mammal such as a human) as defined hereinafter. The therapeutically effective amount or pharmaceutically effective amount varies depending on the subject and the condition to be treated, on the body weight and age of the subject, on the severity of the condition, on the mode of administration, etc., and such amount can be readily determined by one of ordinary skill in the art. For example, the "effective amount", "therapeutically effective amount", or "pharmaceutically effective amount" of the compositions described herein is an amount sufficient to change the expression or activity of YXB1 and thereby treat a subject (e.g., a human) suffering from an indication or to improve or alleviate existing symptoms of the indication. For example, the therapeutically effective amount or pharmaceutically effective amount can be an amount sufficient to reduce the symptoms of a disease or disorder responsive to inhibition of YXB1 activity.

[0167] In some embodiments, the "effective amount" is an amount of a test compound effective to inhibit YB-1 by about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition), at least about 60% (60% inhibition), at least about 70% (70% inhibition), at least about 80% (80% inhibition), or at least about 90% (90% inhibition) when the test compound is administered to an individual, either as a single agent or in combination therapy, in a single dose or multiple doses, as compared to YB-1 activity in an individual not treated with the test compound or as compared to YB-1 activity in the individual before or after treatment with the test compound.

[0168] In some embodiments, an “effective amount” means an amount of a test compound that, when administered to an individual, either singly or in combination, in a single dose or multiple doses, reduces the tumor burden in the individual by about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to the tumor burden in an individual not treated with the test compound, or compared to the tumor burden in the subject before or after treatment with the test compound. As used herein, the term “tumor burden” refers to the total amount of tumor tissue borne by a subject having cancer. In some embodiments, an “effective amount” means an amount of a test compound that, when administered to an individual, either singly or in combination, in a single dose or multiple doses, reduces the radiation dose required to observe tumor shrinkage in the subject by about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to the radiation dose required to observe tumor shrinkage in an individual not treated with the test compound. In some embodiments, an “effective amount” of a compound means an amount that, when administered to an individual having cancer, either singly or in multiple doses, achieves a reduction in tumor size of log1.5, log2, log2.5, log3, log3.5, log4, log4.5, or log5.

[0169] In some embodiments, (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof can be administered at a daily dose of about 0.2 mg / kg to about 10 mg / kg. In other embodiments, this can be administered at a daily dose of about 0.2 mg / kg to about 5 mg / kg.

[0170] In some embodiments, an effective amount of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof is an amount in the range of about 50 ng / kg body weight to about 50 pg / kg body weight (e.g., about 50 ng / kg body weight to about 40 pg / kg body weight, about 30 ng / kg body weight to about 20 pg / kg body weight, about 50 ng / kg body weight to about 10 pg / kg body weight, about 50 ng / kg body weight to about 1 pg / kg body weight, about 50 ng / kg body weight to about 800 ng / kg body weight, about 50 ng / kg body weight to about 700 ng / kg body weight, about 50 ng / kg body weight to about 600 ng / kg body weight, about 50 ng / kg body weight to about 500 ng / kg body weight, about 50 ng / kg body weight to about 400 ng / kg body weight, about 60 ng / kg body weight to about 400 ng / kg body weight, about 70 ng / kg body weight to about 300 ng / kg body weight, about 60 ng / kg body weight to about 100 ng / kg body weight, about 65 ng / kg body weight to about 85 ng / kg body weight, about 70 ng / kg body weight to about 90 ng / kg body weight, about 200 ng / kg body weight to about 900 ng / kg body weight, about 200 ng / kg body weight to about 800 ng / kg body weight, about 200 ng / kg body weight to about 700 ng / kg body weight, about 200 ng / kg body weight to about 600 ng / kg body weight, about 200 ng / kg body weight to about 500 ng / kg body weight, about 200 ng / kg body weight to about 400 ng / kg body weight, or about 200 ng / kg body weight to about 300 ng / kg body weight).

[0171] In some embodiments, an effective amount of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof is an amount in the range of about 10 pg to about 100 mg, which can be, for example, in the range of about 10 pg to about 50 pg, about 50 pg to about 150 pg, about 150 pg to about 250 pg, about 250 pg to about 500 pg, about 500 pg to about 750 pg, about 750 pg to about 1 ng, about 1 ng to about 10 ng, about 10 ng to about 50 ng, about 50 ng to about 150 ng, about 150 ng to about 250 ng, about 250 ng to about 500 ng, about 500 ng to about 750 ng, about 750 ng to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 50 μg, about 50 mg to about 150 mg, about 150 mg to about 250 mg, about 250 mg to about 500 mg, about 500 mg to about 750 mg, about 750 mg to about 1 g, about 1 mg to about 50 mg, about 1 mg to about 100 mg, or about 50 mg to about 100 mg. The amounts described above can be an amount for a single administration or the total amount for one day. The total amount for one day can be in the range of 10 pg to 100 mg, or can be in the range of 100 mg to about 500 mg, or can be in the range of 500 mg to about 1000 mg. In other embodiments, the daily dose or daily amount is 1 mg to 1,000 mg. In other embodiments, the daily dose or daily amount is 10 mg to 1,000 mg. In further embodiments, the daily dose or daily amount is 10 mg to 750 mg. In additional embodiments, the daily dose or daily amount is 10 mg to 500 mg. In additional embodiments, the daily dose or daily amount is 100 mg to 500 mg.

[0172] In some embodiments, a single dose of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof is administered. In other embodiments, multiple doses are administered. When multiple doses are administered over a period of time, the compound may be administered twice a day (qid), once a day (qd), every other day (qod), every three days, three times a week (tiw), or twice a week (biw) over a period of time. For example, the compound may be administered qid, qd, qod, tiw, or biw over a period of one day to about two years or longer. For example, (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof is administered at any of the above frequencies over a period of one week, two weeks, one month, two months, six months, one year, or two years, or longer, depending on various factors.

[0173] Administering an effective amount of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof to an individual having cancer can cause one or more of the following: (1) a decrease in tumor mass; (2) a decrease in the dose of radiation therapy required to cause tumor shrinkage (which may be due to, for example, increased sensitivity to radiation therapy); (3) a decrease in the progression of cancer from one cell to another in an individual; (4) a decrease in morbidity or mortality in a clinical outcome; (5) a shortening of the total duration of treatment when combined with other anti-cancer agents (which may be due to, for example, increased sensitivity to other anti-cancer agents); and (6) an improvement in indicators of disease response (for example, a reduction in one or more symptoms of cancer). To determine whether the treatment method is effective, any of a variety of techniques can be used. For example, a biological sample obtained from an individual treated by the method may be assayed.

[0174] The definitions and conventions used herein with respect to stereochemistry generally follow the following: S. P. Parker, Ed., "McGraw-Hill Dictionary of Chemical Terms" (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds" (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., those compounds have the ability to rotate the plane of polarization of plane-polarized light. When describing an optically active compound, the prefixes D and L, or the prefixes R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, the prefixes D and L, or the prefixes (+) and (-) are utilized to specify the direction of rotation of plane-polarized light by the compound, where S, (-), or l means that the compound is levorotatory, while a compound with the prefixes R, (+), or d is dextrorotatory. For a given chemical structure, such stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which is not optically active.

[0175] As used in reference to enantiomers in this specification, "substantially free of" refers to a composition containing an amount of (S)-(-)-SUO56 that is greater by weight than (R)-(+)-SUO56. In some embodiments, the composition comprises at least 60% by weight of (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof, and 40% or less by weight of (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 70% of (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof, and 30% or less of (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises at least 80% of (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof, and 20% or less of (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In additional embodiments, the composition comprises at least 90% of (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof, and 10% or less of (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 95% of (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof, and 5% or less of (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises at least 98% of (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof, and 2% or less of (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In a further embodiment, the composition comprises at least 99% of (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof, and 1% or less of (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 99.9% of (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof, and 0.1% or less of (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. All of the given percentages regarding the above enantiomers are by weight percentage.

[0176] The relative abundance or concentration of enantiomers may also be characterized as the "enantiomeric excess (ee or EE)" with respect to the degree to which one enantiomer is present in a greater amount than its counterpart. For example, a racemic mixture has an enantiomeric excess of 0%, while a pure enantiomer has an enantiomeric excess of 100%. If a sample has 80% of one enantiomer and 20% of the other, the sample has an enantiomeric excess of 60% (subtracting 20% from 80%). In another aspect, the enantiomeric excess of (S)-(-)-SUO56 relative to (R)-(+)-SUO56 can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, and 99.9%, respectively. In other aspects, the composition contains 100% (S)-(-)-SUO56, and the abundance of (R)-(+)-SUO56 at that time is so low that it cannot be detected by conventional means.

[0177] "Subject" refers to an animal, such as a mammal, that is or can be the subject of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some aspects, the subject is a mammal; in some aspects, the subject is a human; and in some aspects, the subject is selected from cats and dogs. "A subject in need thereof" or "a human in need thereof" refers to a subject, such as a human, who may have or is suspected of having a disease or disorder that can benefit from a treatment as described herein; this is, for example, a treatment using a composition described herein or a pharmaceutically acceptable salt or co-crystal thereof. The subject includes those who may be determined to be at risk of or sensitive to such a disease or disorder, and for which treatment can prevent the onset of the disease or disorder.

[0178] "Treatment" or "treating" is an approach for obtaining beneficial or desirable results, including clinical outcomes. The beneficial or desirable results may include one or more of the following: (i) inhibiting a disease or disorder (e.g., reducing one or more symptoms resulting from the disease or disorder and / or decreasing the severity of the disease or disorder); (ii) blunting or arresting the progression of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying exacerbation or progression of the disease or disorder, and / or preventing or delaying spread (e.g., metastasis) of the disease or disorder); and / or (iii) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., alleviating the condition, providing partial or complete remission of the disease or disorder, enhancing the effect of another therapy, delaying progression of the disease, improving quality of life, and / or extending survival time).

[0179] The terms "inhibit" or "inhibition" mean a decrease in baseline activity of a biological activity or process, e.g., a significant decrease. "Inhibition of YB-1 activity" refers to a decrease in YB-1 activity as a direct or indirect response to the presence of the compositions described herein, which decrease is relative to YB-1 activity in the absence of such a composition or a pharmaceutically acceptable salt or co-crystal thereof. The decrease in activity may be due to a direct interaction between YB-1 and a compound described herein, or may be due to an interaction between a compound described herein and one or more other factors that subsequently affect YB-1 activity. For example, the presence of the compound may decrease YB-1 activity by directly binding to YB-1, the presence of the compound may decrease YB-1 activity by (directly or indirectly) causing another factor that decreases YB-1 activity, or the presence of the compound may decrease YB-1 activity by (directly or indirectly) decreasing the amount of YB-1 present in a cell or organism. In some embodiments, inhibition of YB-1 activity may be compared to the same subject before treatment or to other untreated subjects. The term "inhibitor" is understood to refer to a compound or agent that provides the desired inhibitory activity when administered to a human in a pharmaceutically effective or therapeutically effective dose as needed.

[0180] The term "pharmaceutical composition" refers to a composition comprising a pharmaceutically effective amount of one or more of the isotopic compounds described herein or pharmaceutically acceptable salts thereof, formulated using a pharmaceutically acceptable carrier, which may also contain other additives and which is manufactured or sold under approval by a government regulatory authority as part of a therapeutic regimen for treating a disease in a mammal. Pharmaceutical compositions may be formulated, by way of example, for oral administration as a unit dosage form (e.g., tablets, capsules, caplets, gelcaps, or syrups); for topical administration (e.g., creams, gels, lotions, or ointments); for intravenous administration (e.g., administration as a sterile solution free of particulate embolisms and in a solvent system suitable for intravenous use); or may be formulated to be any other formulation described herein. Conventional procedures and ingredients for selecting and preparing appropriate formulations are described, for example, in: "Remington: The Science and Practice of Pharmacy", 21 st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005); and "The United States Pharmacopeia: The National Formulary" (USP 36 NF31), issued in 2013.

[0181] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable vehicle, which includes, but is not limited to, any carrier, solvent, dispersion medium, coating agent, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents with respect to pharmaceutically active substances is well known in the art. Any conventional medium or agent is intended to be used in a therapeutic composition, except where it is incompatible with the active ingredient. Auxiliary active ingredients may also be incorporated into the composition.

[0182] The term "pharmaceutically acceptable carrier" refers to any component in a pharmaceutical composition other than the disclosed pharmaceutically active compound or therapeutic compound or pharmaceutically acceptable salts thereof (e.g., a carrier capable of suspending or dissolving an active isotopic compound), and having the properties of being non-toxic and non-inflammatory in a patient. Excipients can include, for example: anti-adhesion agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (pigments), emollient agents, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavoring agents, fragrances, fluidizing agents (fluidity improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweetening agents, or water of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methyl cellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propyl paraben, retinol palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, corn starch, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0183] The term "pharmaceutically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Examples of salts can include the following: hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesulfonate (benzenesuflonate) (besylate), p-toluenesulfonate (tosylate), 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate (e.g., acetate, HOOC-(CH2) n -COOH) where n is from 0 to 4). Additionally, when the compounds described herein are obtained as acid addition salts, it is possible to obtain the free base by basifying the solution of the acidic salt. Conversely, when the product is the free base, according to conventional procedures for preparing acid addition salts from basic compounds, the free base can be dissolved in a suitable organic solvent and the solution can be treated with an acid to produce addition salts, particularly pharmaceutically acceptable addition salts. A person skilled in the art is aware of the various synthetic techniques that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0184] The term "crystalline form" and related terms herein refer to the various crystal modifications of a given substance, including but not limited to: its polymorphs, its solvates, its hydrates, its co-crystals, and other molecular complexes thereof, as well as its salts, solvates of its salts, hydrates of its salts, other molecular complexes of its salts, and their polymorphs. The crystalline form of a substance can be obtained by a number of techniques known in the art. Such techniques include but are not limited to: melt recrystallization, dissolution and cooling, solvent recrystallization, recrystallization in a confined space such as in nanopores or capillaries, recrystallization on a surface or template such as on a polymer, recrystallization in the presence of additives such as the co-crystal counter molecule, desolvation, dehydration, rapid evaporation, quenching, slow cooling, vapor diffusion, sublimation, milling, and solvent-drop milling.

[0185] As used herein with respect to cancer, the term "refractory" refers to cancer that does not respond to one or more types of treatment. In some embodiments, the cancer does not respond to one or more types of chemotherapeutic agents. In other embodiments, the cancer does not respond to radiation therapy. In other embodiments, refractory cancer does not respond to one or more types of chemotherapeutic agents and radiation therapy. Refractory cancer may be resistant at the start of such treatment, or may become resistant after the period of one or more types of treatment has ended. In the case of chemotherapy, refractory cancer may also be referred to as "chemotherapy resistant cancer" or "chemo-resistant cancer". "Platinum-resistant cancer" refers to cancer that initially responds to treatment with agents containing the metal platinum, such as cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, and picoplatin, but recurs within a certain period. For example, ovarian cancer that recurs within 6 months after treatment is considered platinum-resistant. With respect to each of the treatment methods herein, there is a further aspect that the cancer is platinum-resistant cancer.

[0186] "Androgen-independent prostate cancer" or "hormone-refractory prostate cancer (AIPC)" refers to prostate cancer that progresses after primary therapy with androgen deprivation by either orchiectomy or a gonadotropin-releasing hormone (LHRH) agonist, followed by administration of an anti-androgen agent and subsequent discontinuation of administration. In some embodiments, hormone-refractory prostate cancer is defined as two or more consecutive increases in prostate-specific antigen (PSA) levels obtained at intervals longer than two weeks, and / or as disease progression documented based on findings from a CT scan and / or a bone scan, bone pain, or symptoms of urinary difficulty. In some embodiments, the PSA level is not elevated at the time of diagnosis and does not increase throughout the course of the disease. In some embodiments, the prostate cancer is inoperable prostate cancer. In some embodiments, the prostate cancer, or prostate cancer with distant metastases, is resistant to treatment with hormone suppression therapy, such as, for example, abiraterone (ZYTIGA®), enzalutamide (XTANDI®), bicalutamide (CASODEX®), flutamide (DROGENIL®), or cyproterone acetate (CYPROSTAT®).

[0187] Cancer cells resistant to radiation therapy are referred to as "radiation resistant cancer" or "radioresistant cancer", whether they were originally resistant or acquired resistance over time. The term is intended to represent cancer cells that have a lower responsiveness to radiation therapy compared to non-resistant cancer cells.

[0188] The ranges and / or limitations disclosed herein are all inclusive of the recited endpoints and are independently combinable. For example, ranges such as "from 2 to 10" and "2 - 10" include the endpoints 2 and 10 and, in the context where the unit is considered, all intermediate values therebetween. For example, references to "claim 2 - 10" or "C2 - C 10 alkyl" include the units 2, 3, 4, 5, 6, 7, 8, 9, and 10, without fractions or decimals, except where described in the context of an average value when the claims and atoms are numbered in consecutive numerical order. On the other hand, in the context of "pH of 5 - 9" or "temperature of 5 degrees - 9 degrees", the integers 5, 6, 7, 8, and 9 are included, as well as fractional or decimal units therebetween, such as 6.5 and 8.24.

[0189] "Significant" means any detectable change that is statistically significant in a standard parametric test for statistical significance, which is, for example, p < 0.05 in a Student's t - test.

[0190] The modifier "about" as used with respect to a quantity encompasses the specified value and has the meaning indicated by the context (e.g., including the degree of error associated with the measurement of a particular quantity). In some embodiments, the term "about" refers to ±10% of the specified quantity. In some embodiments, the term "about" refers to ±5% of the specified quantity.

Examples

[0191] Procedure for synthesizing 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one TIFF2025523065000003.tif62128

[0192] Materials and methods of the experiment: All reagents and solvents were obtained commercially in the highest quality from suppliers such as Sigma-Aldrich, Fisher Scientific, Acros organics, Alfa-Aesar, ChemScene, and Chem-Implex, and they were used without further purification. The reactions were monitored by TLC using pre-coated silica gel plates (Merck, silica gel 60 F254). Flash chromatography was carried out using a CombiFlash Rf+ Lumen chromatography system (Teledyne ISCO, Lincoln, NE, USA). 1H (400 MHz) and 13C (101 MHz) NMR spectra were recorded on either an Agilent 400-MR NMR or a Bruker Avance 400 MHz spectrometer using appropriate deuterated solvents as needed. Chemical shifts (δ) were reported in parts per million (ppm) from high field relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J) were reported in Hertz (Hz), and s, br.s, d, t, and m denote singlet, broad singlet, doublet, triplet, and multiplet, respectively. LC-MS spectra were recorded on an Agilent 6490 iFunnel triple quadrupole mass spectrometer from Agilent Technologies Inc. (Santa Clara, CA, USA). For LC-MS analysis, an Agilent EclipsePlus C18 reverse-phase column, 1.8 μm, 2.1 x 50 mm was used with solvent A (acetonitrile containing 0.1% formic acid) and solvent B (water containing 0.1% formic acid). The ratio of solvent A to solvent B was changed gradually from 1:9 at the start to 9:1 at the end.

[0193] Synthesis of 2-(benzo[d][1,3]dioxol-5-ylamino)ethan-1-ol (2): The compound of the title of TIFF2025523065000004.tif16128 was prepared with some modifications according to the reported methods 1-3. Under a nitrogen atmosphere at room temperature (rt), benzo[d][1,3]dioxol-5-amine (30 g, 0.218 mol) was added to anhydrous dichloromethane (500 mL). To this solution, pyridine (22.49 g, 0.284 mol) and 2-chloroethyl chloroformate (32.8 g, 0.229 mol) were slowly added with stirring. The mixture was stirred at room temperature for 3 hours and then washed with water (4 x 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness using a rotary evaporator. The crude material was dissolved in ethanol (350 mL), treated with NaOH (35 g, 0.875 mol), and heated at 90 °C overnight. The solvent was evaporated by a rotary evaporator. The resulting solid was dissolved in a large amount of ethyl acetate (EtOAc) and then washed successively with water and brine. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to obtain a crude product, which was purified by silica gel column using hexane containing 0-50% gradient of EtOAc to obtain the desired product as a pale brown oil (20 g, 51%).

[0194] Synthesis of 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (“5”, SU-056): The title compound was prepared with some modifications according to the previously reported methods (Kumar, A.; Alegria, A. E., "Synthesis of novel functionalized 4-aza-2,3-didehydropodophyllotoxin derivatives with potential antitumor activity", Journal of heterocyclic chemistry 2010, 47 (6), 1275; Andreoli, M.; Persico, M.; Kumar, A.; Orteca, N.; Kumar, V.; Pepe, A.; Mahalingam, S.; Alegria, A. E.; Petrella, L.; Sevciunaite, L., "Identification of the first inhibitor of the GBP1:PIM1 interaction. Implications for the development of a new class of anticancer agents against paclitaxel resistant cancer cells", Journal of medicinal chemistry 2014, 57 (19), 7916-7932; and Resendez, A.; Tailor, D.; Graves, E.; Malhotra, S. V., "Radiosensitization of Head and Neck Squamous Cell Carcinoma (HNSCC) by a Podophyllotoxin", ACS medicinal chemistry letters 2019, 10 (9), 1314-1321). Under a nitrogen atmosphere, 2-(benzo[d][1,3]dioxol-5-ylamino)ethan-1-ol (16 g, 0.088 mol) of "2", tetronic acid (10.5 g, 0.105 mol) of "3", 3-fluorobenzaldehyde (13.5 g, 0.105 mol) of "4", and L-proline (1.01 g, 0.008 mmol) were added to absolute ethanol (400 mL).The reaction mixture was refluxed overnight. When "2" was consumed, the reaction mixture was evaporated to dryness. The crude product was purified by silica gel column using hexane containing 0 - 50% gradient of EtOAc to obtain the desired product. The product was recrystallized from ethanol to obtain the desired compound (12.1 g, 37%). 1H NMR (400 MHz, DMSO-d6) δ 7.29 (td, J = 7.9, 6.1 Hz, 1H), 7.13 - 6.92 (m, 4H), 6.66 (s, 1H), 5.96 (dd, J = 24.7, 1.1 Hz, 2H), 5.19 - 4.91 (m, 4H), 4.04 - 3.47 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 172.64, 163.93, 161.50, 161.15, 150.33, 150.27, 147.54, 143.77, 131.47, 130.68, 130.60, 124.06, 124.04, 118.96, 114.79, 114.58, 113.71, 113.50, 110.50, 101.90, 96.85, 94.81, 66.34, 58.37, 48.63. LC-MS (ESI-QQQ): m / z 370.1 ([C20H16FNO5 +H]+ calculated value 370.1). Purity > 99.5% (RT 4.35 minutes).

[0195] Separation of enantiomers: The chiral separation of SU-056, which is "5", was achieved by normal-phase HPLC. The normal-phase chiral HPLC analysis was performed on a Waters preparative 150Q LC system, which was equipped with a 2545 quaternary pump, a 2707 automated sample injector, a Waters column heater module, and a 2998 photodiode array detector. The data was collected and processed by Empower 3 software. The enantiomers of SU-056 were separated on a Lux cellulose-4 column [cellulose tris(4-chloro-3-methylphenylcarbamate), 250 X 21.2 mm (ID), 5 μm].

[0196] A quantity of 1.2 g of the racemic compound was dissolved in 6 mL of DMSO, and then 400 μL was injected per run. For the separation of the enantiomers, isocratic elution of 50:50 of solvent A (hexane) and solvent B (ethanol) was used. The flow rate was set at 10 mL / min, the detection wavelength was 320 nm, the runtime was set at 50 minutes, and the temperature of the column oven was set at 40 degrees. Fraction collection was set up by Empower 3 software for collection at a threshold within the window. A set of collection windows was defined (14.0 - 22.0 minutes and 30.0 - 40.0 minutes), and all peaks eluting outside this window were not collected. Enantiomer 1 eluted between 14.0 minutes and 22.0 minutes, and enantiomer 2 eluted between 30.0 minutes and 40.0 minutes. The pure fractions were combined and evaporated to dryness to obtain the desired enantiomers.

[0197] The purity of each enantiomer was confirmed using an analytical column, Lux cellulose-4 column, 100 X 4.6 mm (ID), 5 μm, eluting with a gradient from 3:7 hexane / ethanol to 1:9 hexane / ethanol for the first 5 minutes, followed by a gradient from 1:9 hexane / ethanol to 0.5:9.5 hexane / ethanol for the next 10 minutes. In this gradient, enantiomer 1 and enantiomer 2 eluted at 4.07 minutes and 5.37 minutes, respectively. The purity analysis of each enantiomer based on HPLC showed % purity in UV area of >99% and 95.7% for enantiomer 1 and enantiomer 2, respectively.

[0198] It is understood that the enantiomers of SU056 described herein can be separated using techniques known in the art, including crystallization / recrystallization, diastereomer formation, chiral chromatography, and enzymatic reactions, and may be in the form of salts.

[0199] Figures 1A, 1B, 1C, and 1D show the results of a cell viability assay using the MTT assay in separate triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468, SUM159, and 4T1). The cells were plated in 96-well plates, and the next day, the SU056 mixture, peak 1 of SU056 (D-SU056), and peak 2 of SU056 (L-SU056) were added to the cells at various logarithmic doses (-12.3 to -4.3) and allowed to incubate for 48 hours. At the end of 48 hours, cell viability was measured using the MTT reagent.

[0200] Figures 2A and 2B show the results of a tumor xenograft test for SU056 and its enantiomers in 4T1 tumor xenografts in BALB / c. Mice were subcutaneously injected with 4T1 cells, and treatment with the drug was initiated 3 days after the implantation. The mice were administered either the vehicle (saline containing 40% PEG) or SU056, peak 1 of SU056, and peak 2 of SU056 (50 mg / kg) via the oral route using forced oral administration. (A) Tumor volume (4T1) versus time. (B) Body weight (4T1) versus time.

Claims

**Claim 1** (R)-9-(3-Fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including its optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof, with an enantiomeric excess of (S)-9-(3-Fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including its optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof, a composition comprising. **Claim 3** The composition according to claim 1, wherein the enantiomeric excess is at least 95%. **Claim 4** The composition according to claim 1, wherein the enantiomeric excess is at least 99%. **Claim 5** The composition according to claim 1, wherein the enantiomeric excess is at least 99.9%. **Claim 6** A pharmaceutical composition comprising a pharmaceutically effective amount of the composition according to claim 1 and a pharmaceutically acceptable carrier or excipient. **Claim 7** A method for treating cancer expressing the YB1 protein in a subject, comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition according to any one of claims 1 to 19. **Claim 8** The method according to claim 7, wherein the cancer expressing the YB1 protein is selected from the group consisting of ovarian cancer, endometrial cancer, fallopian tube cancer, and cervical cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, bladder cancer, melanoma, liver cancer, multiple myeloma, soft tissue sarcoma, osteosarcoma, Ewing sarcoma, glioblastoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, kidney cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, head and neck cancer, nasopharyngeal cancer, and gastric cancer. **Claim 9** The cancer in the subject that expresses the YB1 (YBX1) protein is ovarian cancer, and the method further comprises administering a pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof to a subject in need thereof, the method according to claim 8.

10. The method according to claim 9, wherein the taxane compound is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or pharmaceutically acceptable salts thereof.

11. The method according to claim 9, wherein the taxane compound is paclitaxel or a pharmaceutically acceptable salt thereof.

12. The method according to claim 9, wherein the cancer is resistant to treatment with one or more agents from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, and picoplatin.

13. The cancer in the subject that expresses the YB1 (YBX1) protein is breast cancer, and the method further comprises administering a pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof to a subject in need thereof, the method according to claim 8.

14. The cancer in the subject that expresses the YB1 (YBX1) protein is breast cancer, and the method further comprises administering a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, docetaxel, 5-fluorouracil, capecitabine, cyclophosphamide, and carboplatin, or pharmaceutically acceptable salts thereof to a subject in need thereof, the method according to claim 8.

15. The cancer in the subject that expresses the YB1 (YBX1) protein is breast cancer, and the method further comprises administering a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of paclitaxel, albumin-bound paclitaxel, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, and eribulin, or pharmaceutically acceptable salts thereof to a subject in need thereof, the method according to claim 8.

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