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WO 2012/142330 Al 18 October 2012 (18.10.2012) P O P C T

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WO 2012/142330 Al 18 October 2012 (18.10.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2012/142330 Al 18 October 2012 (18.10.2012) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/68 (2006.01) A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, G0 33/574 (2006.01) A61P 35/04 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, PCT/US2012/033386 HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 12 April 2012 (12.04.2012) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/476,056 15 April 201 1 (15.04.201 1) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicants (for all designated States except US): UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, BROWN UNIVERSITY [US/US]; 1 Prospect Street, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Providence, RI 02912 (US). WOMAN & INFANTS' DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, HOSPITAL OF RHODE ISLAND [US/US]; 101 Dudley LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Street, Providence, RI 02905 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/ Applicants (for US only): BRODSKY, Alexan¬ Published: der, S. [US/US]; 34 Harrison Street, Newton, MA 02461 — with international search report (Art. 21(3)) (US). BRARD, Laurent [US/US]; 1608 Toronto Road #12, Springfield, IL 62712 (US). WU, Hsin, Ta [—/US]; — before the expiration of the time limit for amending the 500 Angell, Apt 705, Providence, RI 02906 (US). claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (74) Agents: BEATTIE, Ingrid A. et al; Mintz Levin Cohn Ferris Glovsky And Popeo, P.C., One Financial Center, Boston, MA 021 11 (US). (54) Title: MICRO RNAS AS DIAGNOSTIC BIOMARKERS AND THERAPEUTICS FOR OVARIAN CANCER AND META STATIC TUMORS THAT DISSEMINATE WITHIN THE PERITONEAL CAVITY FIG. 22 © (57) Abstract: The invention provides compositions and methods for predicting metastases of cancer. MICRO RNAS AS DIAGNOSTIC BIOMARKERS AND THERAPEUTICS FOR OVARIAN CANCER AND METASTATIC TUMORS THAT DISSEMINATE WITHIN THE PERITONEAL CAVITY RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No: 61/476,056, filed April 15, 201 1, which is incorporated herein by reference in its entirety. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH This invention was made with Government support under NIH/NCRR grant 5P41RR001395. The Government has certain rights in the invention. FIELD OF THE INVENTION This invention relates generally to the field of cancer. BACKGROUND OF THE INVENTION A biomarker is an identifying or distinguishing characteristic that is objectively measured and evaluated as an indicator of a normal biologic process, pathogenic process, or pharmacologic response to a therapeutic intervention. For example in the context of cancer, a biomarker often refers to a substance or process that is indicative of the presence of cancer in the body. A biomarker might be either a molecule secreted by a tumor or it can be a specific response of the body to the presence of cancer. Genetic, epigenetic, proteomic, glycomic, and imaging biomarkers can be used for cancer diagnosis, prognosis and epidemiology. Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancy, affecting nearly twenty-two thousand women in the United States in 2010, and accounting for nearly fourteen thousand deaths during that year. Serous adenocarcinomas represent the majority of new EOC diagnoses, with most patients presenting symptoms during advanced stages of the disease. Despite removal of the ovaries, surgical debulking, and chemotherapy, most patients with serous EOC will suffer recurrences and ultimately succumb to the disease. Due to the limited efficacy of currently available treatment options for advanced EOC, there is a pressing need to develop new strategies to diagnose and treat ovarian cancer and other metastatic tumors. SUMMARY OF THE INVENTION The invention represents a major advance in the diagnosis, prognosis, and treatment of tumors of the peritoneal cavity by providing micro-ribonucleic acids (microRNAs/miRNAs) that are differentially expressed in primary and metastatic tumors (e.g. , serous epithelial ovarian cancer (EOC)), and which act as biomarkers to predict the severity of cancer and how patients respond to treatment. Specifically, the compositions and methods of the invention predict time to disease progression and overall survival. As such, described herein is the role of post-transcriptional regulation in controlling the spread of cancerous tissue in a subject. The subject is preferably a mammal in need of such treatment, e.g., a subject that has been diagnosed with a primary tumor in an organ or tissue of the peritoneal cavity. The mammal can be, e.g. , any mammal, e.g. , a human, a primate, a mouse, a rat, a dog, a cat, a cow, a horse, or a pig. In a preferred embodiment, the mammal is a human. For example, a composition for predicting presence of secondary site metastases or a predisposition thereto in a subject diagnosed as having a primary tumor comprises a detection reagent specific for at least one microRNA sequence selected from the group consisting of hsa-miR-146a, hsa-miR-150, hsa-miR-193a-5p, hsa-miR-31, hsa-miR-21, hsa-miR-370, hsa- let-7d, hsa-miR-29a, hsa-miR-508-5p, hsa-miR-152, hsa-miR-509-3-5p, hsa-miR-508-3p, hsa-miR-708, hsa-miR-214, hsa-miR-431, hsa-miR-185, hsa-miR-124, hsa-miR-886-3p. Optionally, the composition further comprises a second detection reagent specific for at least one mRNA selected from the group consisting of INTS4, NARS2, SNORD31, INTS2, TRIP10, RASSF2, GADD45B, LTBP2, MYH9, MMP14, PLAU, OLFML2B, THY1, CRISPLD2, COMP, FNDC1, ITGA1 1, IGHM, COL8A1, NNMT, COL1A1, BGN, INHBA, and COL1 1A l (Group I). Alternatively, the composition comprises a detection reagent specific for at least one mRNA selected from the group consisting of FNTS4, NARS2, SNORD31, INTS2, TRIP10, RASSF2, GADD45B, LTBP2, MYH9, MMP14, PLAU, OLFML2B, THY1, CRISPLD2, COMP, FNDC1, ITGA1 1, IGHM, COL8A1, NNMT, COL1A1, BGN, FNHBA, and COL1 1A1 (i.e., in the absence of a detection reagent specific for a microRNA described above). In another example, the composition optionally comprises a second detection reagent specific for at least one mRNA selected from the group consisting of COPZ2, NUCB1, LPL, CCDC49, GFPT2, LOX, NNMT, RGS1, ASNA1, FXYD5, SERPINE1, KIF26B, S100A10, ALDH1A3, CALB2, and PLAUR (Group II). Exemplary compositions for miRNA detection/quantification include those in which the miRNA is selected from the group consisting of hsa-let-7d, hsa-miR-146a, hsa-miR-29a, hsa-miR-193a-5p, hsa-miR-31, hsa-miR-21, hsa-miR-708, hsa-miR-152, hsa-miR-214, and hsa-miR-150. In another example, the miRNA is selected from the group consisting of hsa- let-7d, hsa-miR-146a, hsa-miR-29a, hsa-miR-193a-5p, hsa-miR-31, and hsa-miR-150. In yet another example, the miRNA is selected from the group consisting of hsa-miR-146a, hsa- miR-193a-5p, hsa-miR-31, and hss-miR-150. Combinations of miRNAs are particularly useful. For example, the microRNA comprises a combination of two microRNAS selected from the combinations listed in Table 10, a combination of three microRNAS selected from the combinations listed in Table 11, or a combination of four microRNAS selected from the combinations listed in Table 12. mRNAs are useful as independent prognostic tools and together with miRNAs offer improved prognostic capability. Thus, detection/quantifiction of microRNAs is combined with detection/quantification of one or more mRNAs selected from the group consisting of mRNAs listed in Table 1A or IB. A method for predicting the presence of secondary site metastases or a predisposition thereto in a subject diagnosed as having a primary tumor is carried out by providing a tissue sample obtained from the primary tumor; detecting in the tissue sample at least two biomarkers selected from the group consisting of hsa-miR-146a, hsa-miR-150, hsa-miR- 193a-5p, hsa-miR-31, hsa-miR-21, hsa-miR-370, hsa-let-7d, hsa-miR-29a, hsa-miR-508-5p, hsa-miR-152, hsa-miR-509-3-5p, hsa-miR-508-3p, hsa-miR-708, hsa-miR-214, hsa-miR-43 1, hsa-miR-185, hsa-miR-124, hsa-miR-886-3p; comparing the levels of at least one or two biomarkers in the tissue sample to a control level of the biomarkers, wherein a higher level of at least two biomarkers compared to the control level of the biomarkers indicates that the subject is suffering from or at an increased risk of developing secondary site metastases.
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