(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number Λ (43) International Publication Date / 1 21 July 2011 (21.07.2011) WO 2011/088137 A2 (51) International Patent Classification: Not classified (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, PCT/US201 1/021013 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 12 January 201 1 (12.01 .201 1) HN, HR, HU, ID, JL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (25) Filing Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (30) Priority Data: TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 61/294,1 68 12 January 2010 (12.01 .2010) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): H. LEE kind of regional protection available): ARIPO (BW, GH, MOFFITT CANCER CENTER & RESEARCH IN¬ GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, STITUTE [US/US]; 12902 Magnolia Dr., Tampa, FL ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 33612-9497 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (75) Inventors/ Applicants (for US only): LANCASTER, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Johnathan, M. [US/US]; 15403 Fenton Place, Tampa, GW, ML, MR, NE, SN, TD, TG). FL 33647 (US). CHEN, Dung, Tsa [—/US]; 5077 Southampton Circle, Tampa, FL 33647 (US). XIONG, Published: Yin [CN/US]; 19206 Fishermans Bend Drive, Lutz, FL — without international search report and to be republished 33558 (US). upon receipt of that report (Rule 48.2(g)) (74) Agents: LADWIG, Glenn et al; Saliwanchik, Lloyd & Eisenschenk, P.O. Box 14250, Gainesville, FL 32614-2950 (US). < 00 00 © - © (54) Title: BAD PATHWAY GENE SIGNATURE (57) Abstract: The invention provides materials and methods for prognosing cancer, and predicting an individual's responsiveness ¾ to cancer treatments, methods of treating cancer, and materials and methods for obtaining BAD pathway gene expression profiles useful in carrying out the methods of the invention. DESCRIPTION BAD PATHWAY GENE SIGNATURE CROSS-REFERENCE TO RELATED APPLICATION The present application claims the benefit of U.S. Provisional Application Serial No. 1 294,168, filed January 12, 20 , which is hereby incoiporated b reference herein in its entirety, including any figures, tables, nucleic acid sequences, amino acid sequences, and drawings. GOVERNMENT SUPPORT This invention was made with Government support under Grant No. W81XWH-08-2- 0101 awarded by the Department of Defense (ARMY/MRMC). The Government has certain rights in the invention. BACKGROUND OF THE INVENTION BAD (BCL-2 associated death promoter) is a member of the BCL-2 family of proteins, which are characterized b the presence of up to 4 BCL-2-homology domains (Danial et al. "Cell death: critical control points" Cell, 2004, 116:205-219). This family includes inhibitors and promoters of apoptosis, such that cell survival versus death is determined by the relative ratio of pro-apoptotic (e.g., BCL-Xs, BAD, Bax, Bak) and anti- apoptotic (e.g., Bcl-2, Bcl-xL, MCL-1, Al , BAG-1) family members (Danial et al. "Cell death: critical control points" Cell, 2004, 16:205-219; Dejean et al. "Oligomeric Bax is a component of the putative cytochrome c release channel MAC, mitochondrial apoptosis- induced channel" Mol Biol Cell 2005, 16:2424-2432; Desagher et al. "Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis" J Cell Biol, 1999, 144:891-901; Kuwana et al. "Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane" Cell, 2002, 1:331- 342). BAD selectively hetero-dimerizes with Bcl-xL and Bcl-2 but not with Bax, Bcl-xs, Mc - , Al, or itself. When BAD dimerizes with Bcl-xL, Bax is displaced, mitochondrial membrane permeability increases, and apoptosis is induced (Yang et al. "Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death" Cell, 1995, 80:285-291). However, BAD function is regulated by phosphorylation (including serine- 112, - 136, and -155). When phosphorylated, BAD is unable to heterodimerizc with Bcl-2 or Bcl-xL, freeing Bcl-xL to dimerize and functionally sequestrate Bax, such that it is no longer free to induce apoptosis (Yang et al. "Bad, a heterodimcric partner for Bel-XL and Bcl-2, displaces Bax and promotes cell death" Cell, 1995, 80:285-291 . Thus, the phosphorylation status of BAD determines whether Bax is displaced from Bcl-xL to drive cell death. BAD is thought to be phorphorylated at serine- 136 by protein kinase B (PKB/Akt) (del Peso et al. "Interleukin -3-induced phosphorylation BAD through the protein kinase Akt" Science, 1997, 278:687-689). In contrast, serine-1 12 is phosphorylated by mitogen-activated protein kinase-activated protein kinase- 1 (MAPKAP-K 1, also called RSK) and PKA. Serine- 155. at the center of the BAD BH3 domain, is phosphorylated preferentially by PKA, which also inhibits Bcl-xL binding (Lizcano et al. "Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Serl55" Biochem J, 2000, 349:547-557; Tan et al. "BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival" J Biol Chem, 2000, 275:25865-25869; Zhou et al. "Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Serl55" J Biol Chem, 2000, 275:25046-2505 1 . Conversely, the activity of a series of phosphatases, including PP1, PP2A, and PPM1 (PP2C7PPM1 A) as well as calcineurin, has been shown to have pro-apoptotic effects via de-phosphorylation of BAD (Klumpp et al. "Protein phosphatase type 2C dephosphorylates BAD" Nearachem Int, 2003, 42:555- 560). BRIEF SUMMARY OF THE INVENTION The invention provides biomarkers based on the gene expression of members of the BCL-2 associated death promoter (BAD) pathway, wh h can discriminate between patients with longer versus shorter survival from many human cancers. The present invention relates to the use of genes from the BAD pathway as prognostic biomarkers for various human cancers including but not limited to ovarian cancer, brain cancer, and breast cancer. The invention provides compositions and methods for predicting the development and progression of cancer, and predicting an individual's responsiveness to cancer treatments, methods of treating cancer, and methods of obtaining BAD pathway gene expression profiles useful in carrying out the methods of the invention. The BAD pathway is a critical driver of cellular apoptosis control and a key component of ovarian cancer (OVCA) chemo-sensitivity. A BAD pathway gene expression signature was developed which identified 53 genes in the BAD apoptosis pathway. A pathway score was developed to represent an overall gene expression level for the 53 BAD pathway genes, and subsets thereof. The influence of the BAD pathway expression signature (also referred to herein as a "BAD pathway signature", "BAD pathway score" or simply "pathway score") on cancer patient survival (overall survival or relapse-free survival) for various datasets was evaluated. The BAD pathway expression signature has clinical utility as a prognostic biomarker for various types of cancer. The present invention provides methods and materials (e.g., kits, arrays, and other compositions of matter) for preparing a gene expression profile indicative of cancer prognosis, or cancer chemo-resistance/chemo-sensitivity. In one aspect, the present invention is a method for preparing a gene expression profile indicative of cancer prognosis, comprising: obtaining a biological sample, and determining the level f expression for a plurality of genes of the BCL2 antagonist of cell death (BAD) pathway, thereby preparing the gene expression profile. The sample may be a biological sample from a subject or a cell line, for example. In some embodiments, the prognosis is with respect to at least one factor selected from the group consisting of overall survival, disease- or relapse-free survival, and rate of progression of tumor. In some embodiments, the prognosis is with respect to disease development or progression (e.g., metastasis, transition, tumor size progression, progression from chemo-sensitivity to chemo-resistance). n some embodiments, the prognosis is with respect to survival, and the cancer is selected from among ovarian cancer, breast cancer, colon cancer, and brain cancer. In some embodiments, the prognosis is with respect to development and progression of cancer and the cancer is selected from among breast cancer and endometrial cancer. By predicting the subject ' s prognosis, this aspect of the invention thereby provides information to guide individualized cancer treatment. Preferably, the plurality of genes of the BAD pathway used for the gene expression profile comprises a plurality of genes listed in Table 1. In some embodiments, the plurality of BAD pathway genes is 53 BAD pathway genes, or a subset thereof. In some embodiments, the plurality of BAD pathway genes is 43 BAD pathway genes or 47 BAD pathway genes. In some embodiments, the 53 BAD pathway genes are those represented by U133Plus of Table 1.