(12) United States Patent (10) Patent No.: US 8,178,317 B2 Roberts Et Al

(12) United States Patent (10) Patent No.: US 8,178,317 B2 Roberts Et Al

US008178317B2 (12) United States Patent (10) Patent No.: US 8,178,317 B2 Roberts et al. (45) Date of Patent: May 15, 2012 (54) COMPOSITIONS AND METHODS FOR Mende, I. et al., “Oncogenic Transformation Induced by Membrane IDENTIFYING TRANSFORMING AND Targeted AKT2 and AKT3.” Oncogene 20:4419-4423 (2001). TUMIOR SUPPRESSOR GENES Invitation to Pay Additional Fees and Partial International Search Report dated Oct. 14, 2008 from PCT/US2008/062230. (75) Inventors: Thomas M. Roberts, Cambridge, MA Bamford et al., “The COSMIC (Catalogue of Somatic Mutations in (US); Jean Zhao, Brookline, MA (US); Cancer) database and website.” British Journal of Cancer, 91:355 David E. Hill, Arlington, MA (US); 358 (2004). Bartkova et al., “Cyclin D1 protein expression and function in human William C. Hahn, Newton, MA (US); breast cancer.” Int. J. Cancer, 57(3):353-361 (1994). Jesse Boehm, Jamaica Plain, MA (US) Berger et al., “Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells.” Cancer Research, 64:8867-8875 (73) Assignee: Dana-Farber Cancer Institute, Inc., (2004). Boston, MA (US) Boehm et al., “Transformation of Human and Murine Fibroblasts without Viral Oncoproteins.” Molecular and Cellular Biology, *) Notice: Subject to anyy disclaimer, the term of this 25(15):6464-6474 (2005). patent is extended or adjusted under 35 Brown et al., "Control of IkappaB-alphaproteolysis by site-specific, U.S.C. 154(b) by 233 days. signal-induced phosphorylation.” Science, 267: 1485-1488 (1995). Brunet et al., “Constitutively active mutants of MAP kinase kinase (21) Appl. No.: 12/150,941 (MEK1) induce growth factor-relaxation and oncogenicity when expressed in fibroblasts.” Oncogene, 9(11):3379-3387 (1994). (22) Filed: May 1, 2008 Carroll et al., “The TEL/platelet-derived growth factor B receptor (PDGFBR) fusion in chronic myelomonocytic leukemia is a trans (65) Prior Publication Data forming protein that self-associates and activates PDGFBR kinase US 2009/OO47675A1 Feb. 19, 2009 dependent signaling pathways.” Proc. Natl. Acad. Sci. USA, 93: 14845-14850 (1996). Related U.S. Application Data Chudnovsky et al., “Use of human tissue to assess the oncogenic activity of melanoma-associated mutations.” Nat. Genet., 37(7):745 (60) Provisional application No. 60/927,066, filed on May 749 (2005). 1, 2007. Davies et al., “Mutations of the BRAF gene in human cancer.” Nature, 417:949-954 (2002). (51) Int. Cl. Downward, J., “Targeting RAS signalling pathways in cancer CI2P2/06 (2006.01) therapy.” Nat. Rev. Cancer, 3(1):11-22 (2003). C7H 2L/02 (2006.01) Eisenhaber et al., “Post-translational GPI lipid anchor modification of proteins in kingdoms of life: analysis of protein sequence data (52) U.S. Cl. ...................................... 435/69.1:536/23.1 from complete genomes.” Protein Engineering, 14(1):17-25 (2001). (58) Field of Classification Search ................. 536/23.1; Elenbaas et al., “Heterotypic signaling between epithelial tumor cells 435/69.1 and fibroblasts incarcinoma formation.” Exp. Cell Res., 264(1): 169 See application file for complete search history. 184 (2001). Fan et al., “Homo- and Hetero-Oligomerization of the c-Abl Kinase (56) References Cited and Abelson-linteractor-1.” Cancer Research, 63:873-877 (2003). Farrar et al., “Activation of the Raf-1 kinase cascade by U.S. PATENT DOCUMENTS coumermycin-induced dimerization.” Nature, 383:178-181 (1996). Fitzergerald et al., “IKKepsilon and TBK1 are essential components 5,741,899 A * 4/1998 Capon et al. ................. 536,234 of the IRF3 signaling pathway.” Nat. Immunol. 4(5):491-496 (2003). 6,916,846 B2 7/2005 Farrar et al. Garraway et al., “Integrative genomic analyses identify MITF as a 2004/008 1647 A1* 4/2004 Afeyan et al. .............. 424/94.63 lineage Survival oncogene amplified in malignant melanoma.” FOREIGN PATENT DOCUMENTS Nature, 436:117-122 (2005). WO WO-01/83808 11, 2001 (Continued) OTHER PUBLICATIONS Primary Examiner — Karen Carlson Golubet al. 1994: Fusion of PDGF receptor to a novelets-like gene, (74) Attorney, Agent, or Firm — Foley Hoag LLP tel, in chronic myelomonocytic leukemia with t(5; 12) chromosomal translocation. Cell. 77:307-316. (57) ABSTRACT Maeda et al. 2005, published on-line 2004; Transforming property of TEL-FGFR3 mediated through P13-K in a T-cell lymphoma that Provided herein are nucleic acids, proteins, vectors, cells, Subsequently progressed to aML. Blood 105(5):2115-2123.* kits, devices and methods useful for identifying regulatable Jarvik et al. 1998; Epitope tagging. Annual Review of Genetics. proteins that are able to complement components of cellular 32:601-618. signaling pathways. Also provided are compositions and McWhirter et al. 1993: A coiled-coil oligomerization domain of Bcr methods using these complementing genes directly as mark is essential for the transforming function of Bcr-ABL oncoproteins. ers for cancer diagnosis or prognosis and as targets for anti Molecular and cellular Biology. 13(12): 7587-7595.* Aoki, M. et al., “The AKT Kinase: Molecular Determinants of neoplastic therapeutics. Further provided are methods for Oncogenicity.” Proc. Natl. Acad. Sci. 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