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WO 2014/028907 Al 20 February 2014 (20.02.2014) 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 2014/028907 Al 20 February 2014 (20.02.2014) P O P C T (51) International Patent Classification: (74) Agents: EVANS, Judith et al; P.O. Box 23 1, Manassas, C12Q 1/68 (2006.01) G01N 33/00 (2006.01) VA 20108 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 13/055469 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 16 August 2013 (16.08.2013) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 61/684,029 16 August 2012 (16.08.2012) US SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 61/718,468 25 October 2012 (25. 10.2012) US TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 61/745,207 2 1 December 2012 (21. 12.2012) US ZW. (71) Applicant: THE TRUSTEES OF COLUMBIA UNI¬ (84) Designated States (unless otherwise indicated, for every VERSITY IN THE CITY OF NEW YORK [US/US]; kind of regional protection available): ARIPO (BW, GH, 412 Low Memorial Library, 535 West 116th Street, New GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, York, NY 10027 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: ABATE-SHEN, Corrine; 737 Saint Nicholas EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Ave., New York, NY 10031 (US). SHEN, Michael; 737 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Saint Nicholas Ave., New York, NY 1003 1 (US). CALI- TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, FANO, Andrea; 25 1 West 19th Street, Apt. 8c, New York, KM, ML, MR, NE, SN, TD, TG). NY 1001 1 (US). KANTH, Shazia, Irshad; 4 Conifer Close, Orpington BR6 9QD (GB). BANSAL, Mukesh; Declarations under Rule 4.17 : 501 West 107th Street, Apt. Gdn, New York, NY 10032 — as to applicant's entitlement to applyfor and be granted a (US). patent (Rule 4.1 7(H)) [Continued on nextpage] (54) Title: DIAGNOSTIC MARKERS OF INDOLENT PROSTATE CANCER I I I o FIG. 1 00 o (57) Abstract: A 3-gene prognostic panel has been identified that together accurately predicted the outcome of low Gleason score o prostate tumors as either truly indolent or at a high risk of becoming aggressive. The 3-gene prognostic panel was validated on inde pendent cohorts confirmed its independent prognostic value, as well as its ability to improve prognosis with currently used clinical nomograms. Expression of the 3-gene prognostic panel was determined by quantifying mRNA or protein encoded by the panel (col o lectively referred to as "prognostic biomarkers"). The prognostic biomarkers were discovered to be up-regulated in indolent tumors and down-regulated in aggressive forms of prostate cancer. w o 2014/028907 Al II II II I III IIII II II I II III II lllll II I II — as to the applicant's entitlement to claim the priority of — before the expiration of the time limit for amending the the earlier application (Rule 4.17(Hi)) claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) Published: DIAGNOSTIC MARKERS OF INDOLENT PROSTATE CANCER CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit of Provisional Appln. 61/684,029, filed 8/16/2012, and Provisional Appln. 61/718,468, filed 10/25/2012, and Provisional Appln. 61/745,207, filed 12/21/2012, the entire contents of which are hereby incorporated by reference as if fully set forth herein, under 35 U.S.C. §119(e). STATEMENT OF GOVERNMENT SUPPORT [0002] This invention was made with government support under Grant Nos. R01CA076501, CA154293, CA084294 and CA121852 awarded by the National Cancer Institute, and a Silico Research Centre of Excellence NCI-caBIG, SAIC 29XS192 grant awarded by the National Cancer Institute. Thus, the United States Government has certain rights in the present invention. BACKGROUND OF THE INVENTION [0003] With over 200,000 new diagnoses per year (7), prostate cancer is one of the most prevalent forms of cancer in aged men. Several factors, including an increase in the aging population and widespread screening for prostate specific antigen (PSA), have contributed to a substantial rise in diagnoses of early-stage prostate tumors, many of which require no immediate therapeutic intervention (2-4). Indeed, the primary means of determining the appropriate treatment course for men diagnosed with prostate cancer still relies on Gleason grading, a histopathological evaluation that lacks a precise molecular correlate (5). While patients presenting with biopsies of high Gleason score (Gleason >8) tumors are recommended to undergo immediate treatment, determining the appropriate treatment for those with biopsies of low (Gleason 6) or even intermediate (Gleason 7) Gleason score tumors can be more ambiguous. [0004] Currently, there is the potential for overtreatment of patients who have indolent prostate cancer (e.g., low-risk, non-aggressive or non-invasive cancers) who would not have died of the disease if left untreated (4, 6-8). Consequently, the practice of "watchful waiting" (9) or, more recently, "active surveillance" (10-12) has emerged as an alternative for monitoring men with potentially low risk prostate cancer, with the intention of avoiding treatment unless there is evidence of disease progression. The advantage is to minimize overtreatment; however, the obvious risk is that active surveillance may miss the opportunity for early intervention of tumors that are seemingly low risk but are actually aggressive. Thus, there is a critical need to identify biomarker panels that distinguish the majority of low Gleason score tumors that will remain indolent from the few that are truly aggressive. Unfortunately, so far prostate cancer, unlike many other cancer types, has proven remarkably resilient to classification into molecular subtypes associated with distinct disease outcomes (13, 14). Additionally, an inherent lack of understanding of the biological processes that distinguish indolence from aggressiveness has represented a considerable limitation for identifying relevant biomarkers. SUMMARY OF THE INVENTION [0005] Certain embodiments are directed to methods for determining if an indolent epithelial cancer is at a high risk of progressing to an aggressive cancer. More specifically, the method comprises (a) identifying a subject having indolent epithelial cancer, (b) obtaining a test biological sample of the epithelial cancer from the subject and a control sample of benign noncancerous prostate tissue from the subject or from a normal subject, (c) detecting a level of expression of a prognostic mRNA or protein encoded by each of three prognostic genes selected from the group consisting of FGFR1, PMP22, and CDKN1A in the test sample, as compared to the level of expression in the control sample, and (d) if the level of expression of the mRNA or a protein or both is the same or higher than the corresponding level in the control, then determining that the epithelial cancer is indolent, and if there is about a two-fold or greater decrease in the level of expression of the mRNA or protein compared to the control then determining that the epithelial cancer is at high risk of progressing to an aggressive form. In some embodiments the epithelial cancer is prostate cancer with a Gleason score of 7 or less, breast cancer or lung cancer. In another embodiment the method further includes (e) treating the subject if it is determined that the indolent cancer is at a high risk of progressing toward an aggressive form the biological sample is blood, plasma, urine or cerebrospinal fluid [0006] Another embodiment is directed to a method for determining if a subject who has an indolent cancer has progressed or is progressing to an aggressive form of cancer by (a) identifying a subject having indolent epithelial cancer, (b) obtaining a first biological sample of the indolent cancer from the subject at a first time point and a second biological sample at a second time point; (c) determining a level of expression of a prognostic mRNA or protein or both encoded by each of three prognostic genes selected from the group consisting of FGFR1, PMP22, and CDKN1A in the first and second samples at the respective first and second time points, (d) comparing the expression levels of the prognostic mRNA or protein at the first time point to the expression levels at the second time point, and (e) determining that the indolent cancer is not progressing to an aggressive form if the level of expression of the prognostic mRNA or the protein or both at the second time point is the same or greater than at the first time point, and determining that the indolent cancer is at a high risk of progressing toward an aggressive form if there is about a two-fold or greater decrease in the level of expression of the prognostic mRNA or a protein at the second time point compared to the levels at the first time point.
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