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(12) United States Patent (10) Patent No.: US 8.440,393 B2 Birrer Et Al

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(12) United States Patent (10) Patent No.: US 8.440,393 B2 Birrer Et Al USOO8440393B2 (12) United States Patent (10) Patent No.: US 8.440,393 B2 Birrer et al. (45) Date of Patent: May 14, 2013 (54) PRO-ANGIOGENIC GENES IN OVARIAN OTHER PUBLICATIONS TUMORENDOTHELIAL CELL, SOLATES Boyd (The Basic Science of Oncology, 1992, McGraw-Hill, Inc., p. (75) Inventors: Michael J. Birrer, Mt. Airy, MD (US); 379). Tomas A. Bonome, Washington, DC Tockman et al. (Cancer Res., 1992, 52:2711s-2718s).* (US); Anil Sood, Pearland, TX (US); Pritzker (Clinical Chemistry, 2002, 48: 1147-1150).* Chunhua Lu, Missouri City, TX (US) Benedict et al. (J. Exp. Medicine, 2001, 193(1) 89-99).* Jiang et al. (J. Biol. Chem., 2003, 278(7) 4763-4769).* (73) Assignees: The United States of America as Matsushita et al. (FEBS Letters, 1999, vol. 443, pp. 348-352).* Represented by the Secretary of the Singh et al. (Glycobiology, 2001, vol. 11, pp. 587-592).* Department of Health and Human Abbosh et al. (Cancer Res. Jun. 1, 2006 66:5582-55.91 and Supple Services, Washington, DC (US); The mental Figs. S1-S7).* University of MD Anderson Cancer Zhai et al. (Chinese General Practice Aug. 2008, 11(8A): 1366 Center, Houston, TX (US) 1367).* Lu et al. (Cancer Res. Feb. 15, 2007, 64(4): 1757-1768).* (*) Notice: Subject to any disclaimer, the term of this Bagnato et al., “Activation of Mitogenic Signaling by Endothelin 1 in patent is extended or adjusted under 35 Ovarian Carcinoma Cells', Cancer Research, vol. 57, pp. 1306-1311, U.S.C. 154(b) by 194 days. 1997. Bouras et al., “Stanniocalcin 2 is an Estrogen-responsive Gene (21) Appl. No.: 12/541,729 Coexpressed with the Estrogen Receptor in Human Breast Cancer', Cancer Research, vol. 62, pp. 1289-1295, 2002. (22) Filed: Aug. 14, 2009 Bryant et al., “EZH2 promotes proliferation and invasiveness of (Under 37 CFR 1.47) prostate cancer cells'. Prostate, vol. 67, No. 5, pp. 547-556, 2007. Bumgardner et al., "Chitosan: potential use as a bioactive coating for (65) Prior Publication Data orthopaedic and craniofacial f dental implants'. J. Biomater: Sci. US 2010/0286237 A1 Nov. 11, 2010 Polymer Edn, vol. 14, No. 5, pp. 423-438, 2003. Carson-Walter et al., “Cell surface tumor endothelial markers are conserved in mice and humans'. Cancer Res., vol. 61, No. 18, pp. Related U.S. Application Data 6649-6655, 2001. Chang et al., “The Murine Stanniocalcin 1 Gene Is Not Essential for (63) Continuation-in-part of application No. PCT/US2008/ Growth and Development'. Molecular and Cellular Biology, vol. 25. 054014, filed on Feb. 14, 2008. No. 23, pp. 10604-10610, 2005. Conejo-Garcia et al., “Vascular leukocytes contribute to tumor (60) Provisional application No. 60/901,455, filed on Feb. vascularization”. Blood, vol. 105, No. 2, pp. 679-681, 2005. 14, 2007. Donninger et al., “Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways'. (51) Int. Cl. Oncogene, vol. 23, No. 49, pp. 8065-8077, 2004. CI2O I/00 (2006.01) Dupraz et al., “Characterization of silane-treated hydroxyapatite CI2O I/68 (2006.01) powders for use as filler in biodegradable composites'. Journal of GOIN33/53 (2006.01) Biomedical Materials Research, vol. 30, pp. 231-238, 1996. GOIN33/567 (2006.01) GOIN33/574 (2006.01) (Continued) CI2N IS/II (2006.01) (52) U.S. Cl. USPC ................ 435/4; 435/6.1; 435/6.14; 435/7.1; Primary Examiner — Peter J Reddig 435/721: 435/723: 514/44. A (74) Attorney, Agent, or Firm — Klarduist Sparkman, LLP (58) Field of Classification Search ........................ None See application file for complete search history. (57) ABSTRACT (56) References Cited A gene profiling signature for ovarian tumor endothelial cells is disclosed herein. The gene signature can be used to diag U.S. PATENT DOCUMENTS nosis or prognosis an ovarian tumor, identify agents to treat an 2003/0186909 A1 10/2003 McSwiggen ovariantumor, to predict the metastatic potential of an ovarian 2005/OO37389 A1 2/2005 Santin tumor and to determine the effectiveness of ovarian tumor 2005/0059682 A1* 3, 2005 Rubinfeld .................. 514,263.1 2006/0094.046 A1 5, 2006 Abo et al. treatments. Thus, methods are provided for identifying agents 2006/0.104981 A1* 5, 2006 Hikichi et al. ............. 424,155.1 that can be used to treat ovarian cancer, for determining the effectiveness of an ovarian tumor treatment, or to diagnose or FOREIGN PATENT DOCUMENTS prognose an ovarian tumor. Methods of treatment are also WO WO O2O83874 10, 2002 disclosed which include administering a composition that WO WOO3O80800 10, 2003 includes a specific binding agent that specifically binds to one WO WO 2004OO5883 1, 2004 of the disclosed ovarian endothelial cell tumor-associated WO WO 2004O15396 2, 2004 WO WO 2004 108896 12, 2004 molecules and inhibits ovarian tumor in the Subject. WO WO 2006085746 8, 2006 WO WO 2006138275 12/2006 WO WO 2007O16367 2, 2007 7 Claims, 20 Drawing Sheets US 8.440,393 B2 Page 2 OTHER PUBLICATIONS Narita et al., “Analysis of Heat Shock Related Gene Expression in Head-And-Neck Cancer Using cDNA Arrays'. Int. J. Radiation Garcia et al., “2-Methoxyestradiol Inhibits Prostate Tumor Develop Oncology Biol. Phys, vol. 53, No. 1, pp. 190-196, 2002. ment in Transgenic Adenocarcinoma of Mouse Prostate: Role of Tumor Necrosis Factor-O-Stimulated Gene 6', Clin Cancer Res, vol. Reedijk et al., “High-level Coexpression of JAG1 and NOTCH1 is 12, No. 3, pp.980-988, 2006. Observed in Human Breast Cancer and is Associated with Poor Halder et al., “Focal Adhesion Kinase Targeting Using In vivo Short Overall Survival”, Cancer Research, vol. 65, No. 18, pp. 8530-8537, Interfering RNA Delivery in Neutral Liposomes for Ovarian Carci 2005. noma Therapy”, Clin Cancer Res, vol. 12, No. 16, pp. 4916-4924, Voutilainen et al., “Versican in Epithelial Ovarian Cancer: Relation to 2006. Hyaluronan, Clinicopathologic Factors and Prognosis'. Int. J. Can Kleer et al., “EZH2 is a marker of aggressive breast cancer and cer, vol. 107, pp. 359-364, 2003. promotes neoplastic transformation of breast epithelial cells'. PNAS, Wang et al., “Identification of a novel function of TWIST, a bHLH vol. 100, No. 20, pp. 11606-11611, 2003. Lemaire et al., “Loss of HOP tumour suppressor expression in head protein, in the development of acquired taxol resistance in human and neck Squamous cell carcinoma'. British Journal of Cancer, vol. cancer cells'. Oncogene, vol. 23, No. 2, pp. 474-482, 2004. 91, pp. 258-261, 2004. Weiner et al., “Decreased Src Tyrosine Kinase Activity Inhibits Lu et al., “Selection of Potential Markers for Epithelial Ovarian Malignant Human Ovarian Cancer Tumor Growth in a Nude Mouse Cancer with Gene Expression Arrays and Recursive Descent Parti Model”, Clinical Cancer Research, vol. 5, pp. 2164-2170, 1999. tion Analysis”. Clinical Cancer Research, vol. 10, pp. 3291-3300. Yeung et al., "Cloning of a novel epidermal growth factor repeat 2004. Mok et al., “Biomarker Discovery in Epithelial Ovarian Cancer by containing gene EGFL6: expressed in tumor and fetal tissues'. Genomic approaches'. Advances in Cancer Research, vol. 96, pp. Genomics, vol. 62, No. 2, pp. 304-307, 1999. 1-22, 2006. Yeung et al., “Hypoxia-Inducible Factor-1-Mediated Activation of Nanda et al., “Identification of a Binding Partner for the Endothelial Stanniocalcin-1 in Human Cancer Cells'. Endocrinology, vol. 146, Cell Surface Proteins TEM7 and TEM7R, Cancer Research, vol. 64, No. 11, pp. 4951-4960, 2005. pp. 8507-851 1, 2004. Zhang et al., “Down-regulation of Jagged-1 induces cell growth Nanjundan et al., “Identification of a novel splice variant of AML1b inhibition and S phase arrest in prostate cancer cells'. Int. J. Cancer, in ovarian cancer patients conferring loss of wild-type tumor Sup vol. 119, pp. 2071-2077, 2006. pressive functions'. Oncogene, vol. 26, No. 18, pp. 2574-2584, E-published 2006. * cited by examiner U.S. Patent May 14, 2013 Sheet 1 of 20 US 8.440,393 B2 WoW WN30 W . i gous valloo : x: 9Wg.TOO pop- zuwwav :::: ZsodSo 9W. N. Xid : on 1903 efuelo po affe env U.S. Patent May 14, 2013 Sheet 2 of 20 US 8.440,393 B2 Normal PTK2 Fyn MMP-9 32-arrestin Jagged 1 PLXDC1 2 4 6 Fold change (OD) U.S. Patent May 14, 2013 Sheet 3 of 20 US 8.440,393 B2 OOOO % CN ais U.S. Patent May 14, 2013 Sheet 4 of 20 US 8.440,393 B2 000;,00800900€0 ?od?uolo40% U.S. Patent May 14, 2013 Sheet 5 of 20 US 8.440,393 B2 CN N s U.S. Patent May 14, 2013 Sheet 6 of 20 US 8.440,393 B2 Tumor Nodules s G CO a. D GS) Tumor weight (g) U.S. Patent May 14, 2013 Sheet 7 of 20 US 8.440,393 B2 Tumor weight (g) U.S. Patent May 14, 2013 Sheet 8 of 20 US 8.440,393 B2 –(+-- Tumor weight (g) Number of Nodules 9"SDI U.S. Patent May 14, 2013 Sheet 9 of 20 US 8.440,393 B2 0 5 10 15 20 25 Follow-up (years) tra 2 s sw *3. ow EAH2 s s *. Edo Wils * ... s * High Ezh2. 2 -X. Endo s 0 5 10 15 20 25 Follow-up (years) 5 s EZH2-Endo U.S. Patent May 14, 2013 Sheet 10 of 20 US 8.440,393 B2 F.G. 8 *p-0.05 **pz0.01 **pz0.001 p-value 0.0319 ©iNº. 10 EZH2 microarray expression (log2) U.S. Patent May 14, 2013 Sheet 11 of 20 US 8.440,393 B2 WASH1 Prooter C: control; W: VEGF (50 ng M-) c is a g EZH2 is Histone 3 (ys 27) Actin S.d WASH WASH1W 6 : 0.08 Contro VEGF - EZH2 siRNA VEGF SiRNA U.S.
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