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WO 2012/170640 Al 13 December 2012 (13.12.2012) P O P C T

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WO 2012/170640 Al 13 December 2012 (13.12.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/170640 Al 13 December 2012 (13.12.2012) P O P C T (51) International Patent Classification: (74) Agent: BOCK, Joel N. /Joel N. Bock, Reg. No. 36456/; C12Q 1/68 (2006.01) SNR DENTON US LLP, P.O. Box 061080, Wacker Drive Station, Willis Tower, Chicago, Illinois 60606 (US). (21) International Application Number: PCT/US20 12/04 1267 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) Date: International Filing AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, 7 June 2012 (07.06.2012) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 61/494,183 7 June 201 1 (07.06.201 1) US OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (71) Applicant (for all designated States except US): THE TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK [US/US]; 412 Low Library, Mail (84) Designated States (unless otherwise indicated, for every Code 4308, 535 West 116th Street, New York, New York kind of regional protection available): ARIPO (BW, GH, 10027 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (72) Inventors; and TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (75) Inventors/Applicants (for US only): VUNDAVALLI, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Murty [US/US]; 560 Riverside Drive, Apartment 10H, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, New York, New York 10027 (US). XIE, Dongxu TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, [US/US]; 3475 Greystone Avenue, Apartment 2B, Bronx, ML, MR, NE, SN, TD, TG). New York 10463 (US). BHAGAT, Govind [US/US]; 250 Cabrini Boulevard, Apartment 7A, New York, New York Published: 10033 (US). — with international search report (Art. 21(3)) (54) Title: METHODS AND COMPOSITIONS FOR TRAIL-DRUG COMBINATION THERAPY (57) Abstract: Provided are methods for diagnosing conditions, such as cervical cancer, T-cell hematologic malignancies, B-cell NHL or breast cancer, susceptible to increased TRAIL-mediated apoptosis. Diagnosis can include the presence of one or more of an 8p chromosomal deletion, methylation-associated decoy receptor inactivation, or decreased decoy receptor expression. Also provided are methods of treatment and compound screening related to TRAIL-mediated apoptosis. Also provided are methods of treatment and compound screening related to cervical cancer, T-cell hematologic malignancies, B-cell NHL or breast cancer. METHODS AND COMPOSITIONS FOR TRAIL-DRUG COMBINATION THERAPY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application Serial No. 61/494,183, filed on June 7, 201 1, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant number CA095647 awarded by National Institutes of Health. The government has certain rights in the invention. MATERIAL INCORPORATED-BY-REFERENCE The Sequence Listing, which is a part of the present disclosure, includes a computer readable form comprising nucleotide and/or amino acid sequences of the present invention. The subject matter of the Sequence Listing is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Cervical Cancer (CC) affects over 0.5 million women worldwide. When invasive cancer is diagnosed the cure rate is low resulting in high mortality and the treatment response remains unpredictable. Over 90% of invasive cervical cancer and Cervical Intraepithelial Neoplasia (CIN) contain human papilloma virus (HPV) DNA sequences. The high-risk HPV (hrHPV) type E6 and E7 proteins interact with critical cell cycle checkpoint genes p53 and pRb, respectively, interfere with the DNA repair mechanisms, as a consequence accelerate the accumulation of genetic alterations and immortalization (1). Conventional treatment of cervical cancer often employs chemotherapy using platinum based derivatives followed by radiation. But cervical cancer as a single diagnostic entity exhibits differences in clinical behavior and response to therapy, where advanced tumors remain unresponsive to chemo-radiotherapy. Cisplatin is used as the most effective agent in advanced stages of cervical cancer where most patients exhibit acquired resistance or progressive disease after initial response (2). B-cell Non-Hodgkin Lymphoma (B-NHL) subtypes exhibit complex genetic changes that include characteristic chromosome translocations. Although recent molecular studies have identified certain prognostic markers, the low (<50%) progression- free survival achieved currently in high grade lymphomas such as diffuse large-B-cell lymphoma (DLBCL) is primarily due to lack of understanding of the complex genetic and epigenetic lesions in these subtypes of B-NHL. Moreover, the yield of potential therapeutic targets discovered to date has been limited. Although overall survival has been significantly improved for B-cell lymphomas by the addition of rituximab, a large proportion of B-NHL patients still exhibit resistance to the existing treatments [34]. Therefore, there is a need for developing new therapies and biomarker of response to stratify patients that benefit specific treatments such as TRAIL combination drugs. A majority of breast cancer patients exhibit resistance to either recombinant TRAIL or antibodies targeting TRAIL-R1/TRAIL-R2 despite the expression of death receptors on the cell surface [35]. The exact mechanisms of resistance in breast cancer patients are not well understood. Breast cancer is one of the top 3 cancers that exhibit 8p21 .3 region deletions (at a proportion of 0.59) and exhibit frequent promoter methylation of either DcR1 or DcR2 genes [16, 36]. Although breast cancer as a group exhibits resistance to commonly used chemotherapy drugs such as doxorubicin and tomoxifen, patients with ER+ phenotype are the most resistant [37]. The underlying genetic determinants of TRAIL resistance/sensitivity in breast cancer cells are not known. We hypothesize that 8p deletion and decoy receptor inactivation may play a role in sensitizing breast cancer cells to TRAIL combination drug therapy. Therefore, these suboptimal outcomes of conventional treatments in breast cancer patients warrants an urgent need for the development of new therapies and identify biomarker to stratify patients that predict response to specific drug therapy. T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) and Peripheral T-cell lymphoma (PTCL) are a heterogeneous group of disorders committed to the T-cell lineage and represent distinct clinico-pathologic entities. Although chromosome abnormalities that generate fusion genes and alter genetic pathways e.g. INK4, NOTCH1, WT1, PTEN, PHF6 have been identified in a proportion of cases, their relationship with outcome is unclear [3-7]. Despite intensive risk-adopted chemotherapy protocols, the majority of T- cell leukemia/lymphoma (TCL) as a group exhibit resistance to therapy and shorter long- term disease-free survival with the exception of ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) that exhibit high cure rates with CHOP-like therapy. For example, studies using anthracycline-containing regimens PTCL show only 32% cases with 5-year overall survival [5, 8]. The suboptimal outcome using intensive therapies for newly diagnosed TCL patients suggest that the current standard therapies are not effective and, therefore there is an urgent need for the development of new therapies. It has been recited in the art that "[m]uch effort has been devoted but failed to identify the biomarker(s) that can predict the sensitivity of human cancers to TRAIL-based therapies" and "it may be difficult if not impossible to identify the biomarkers that could predict the drug responsiveness in such genetically diversified [cancer]" (Bellail et al. 2009 4, 34-41, at 38). Death receptor ligands, Fas and tumor necrosis factor (TNF)-related apoptosis- inducing ligand (TRAIL), play a role in cytotoxic T cell (CTC) and natural killer (NK) cell- mediated anti-tumor immunity. TCL cells acquire mechanisms to escape the host immune surveillance [9]. Despite the availability of novel genomic data and alterations of the associated genetic pathways, stratification of T-cell malignancies into subclasses responsive to specific treatment regimens is not feasible with agents currently being used [2, 10]. Tumor necrosis factor related super family (TNFRSF) of death receptors DR4 and DR5 express on the cell surface and are critical regulators of the extrinsic apoptotic pathway in TRAIL/AP02L-mediated cell death. Binding of TRAIL to their cognate DRs results in death inducing signaling complex (DISC) formation and DISC initiates activation of proteases caspase 8 and 10, thereby driving downstream effector caspase activation and apoptosis. TRAIL as a soluble zinc -coordinated homotrimeric protein triggers apoptosis only in cancer cells without affecting normal cells. Despite this specificity, many human cancers exhibit resistance to TRAIL [ 1 1, 12]. Since decoy receptors DcR1 and DcR2 compete with death receptors DR4 and DR5 in binding with TRAIL, over expression of DcR1 and DcR2 protects tumor cells from TRAIL-induced apoptosis. Efforts to identify differences in TRAIL responsiveness in tumor cells has identified decreased stimulation of TRAILR1 or R2 by DcRs, suppression of the intracellular signaling cascade genes, and post-translational modifications as important predictors [12, 22].
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