Research Projects

updated 12.17.2013

Project 1: Role of Gene Fusions in Prostate Cancer

Co-Leader: Arul Chinnaiyan, M.D., Ph.D.going to a new website
Co-Leader: James E. Montie, M.D.going to a new website

The translational goal of this project is to develop a molecular sub-type classification for prostate cancer similar to what has been done for certain leukemias and lymphomas. It is envisioned that these gene fusion based molecular sub-types will be useful in predicting prognosis and therapy for prostate cancer patients.

Specific Aims

1. Characterization of Oncogenic ETS Gene Fusions in Prostate Cancer. The goal of this Aim was to develop the necessary tools to enable the systematic identification of ETS gene fusions in prostate cancers including gene fusion and variants.

2. Determine the role of ETS family gene fusions in prostate cancer cell lines. Here we proposed to over-express ERG and ETV1 in benign prostate epithelial cells, and knock down ETS gene fusions in appropriate prostate cancer cell lines.

3. Characterize the phenotype of androgen-regulated ETS transgenic mice. Here we will systematically analyze the androgen-regulated ERG and ETV1 transgenic mice we created.

Major Publications:

  1. Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, Patel S, Wang X, Liang H, Yu J, Palanisamy N, Siddiqui J, Yan W, Cao X, Mehra R, Sabolch A, Basrur V, Lonigro RJ, Yang J, Tomlins SA, Maher CA, Elenitoba-Johnson KS, Hussain M, Navone NM, Pienta KJ, Varambally S, Feng FY, Chinnaiyan AM. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011 May 17;19(5):664-78. PubMed PMID: 21575865; PubMed Central PMCID: PMC3113473.

  2. Tomlins SA, Aubin SM, Siddiqui J, Lonigro RJ, Sefton-Miller L, Miick S, Williamsen S, Hodge P, Meinke J, Blase A, Penabella Y, Day JR, Varambally R, Han B, Wood D, Wang L, Sanda MG, Rubin MA, Rhodes DR, Hollenbeck B, Sakamoto K, Silberstein JL, Fradet Y, Amberson JB, Meyers S, Palanisamy N, Rittenhouse H, Wei JT, Groskopf J, Chinnaiyan AM. Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci Transl Med. 2011 Aug 3;3(94):94ra72. PubMed PMID: 21813756; PubMed Central PMCID: PMC3245713.

  3. Roychowdhury S, Iyer MK, Robinson DR, Lonigro RJ, Wu YM, Cao X, Kalyana-Sundaram S, Sam L, Balbin OA, Quist MJ, Barrette T, Everett J, Siddiqui J, Kunju LP, Navone N, Araujo JC, Troncoso P, Logothetis CJ, Innis JW, Smith DC, Lao CD, Kim SY, Roberts JS, Gruber SB, Pienta KJ, Talpaz M, Chinnaiyan AM. Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci Transl Med. 2011 Nov 30;3(111):111ra121. doi:10.1126/scitranslmed.3003161. PubMed PMID: 22133722; PubMed Central PMCID: PMC3476478.

  4. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, Quist MJ, Jing X, Lonigro RJ, Brenner JC, Asangani IA, Ateeq B, Chun SY, Siddiqui J, Sam L, Anstett M, Mehra R, Prensner JR, Palanisamy N, Ryslik GA, Vandin F, Raphael BJ, Kunju LP, Rhodes DR, Pienta KJ, Chinnaiyan AM, Tomlins SA. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012 Jul 12;487(7406):239-43. doi: 10.1038/nature11125. PubMed PMID: 22722839; PubMed Central PMCID: PMC3396711.

  5. Prensner JR, Iyer MK, Sahu A, Asangani IA, Cao Q, Patel L, Vergara IA, Davicioni E, Erho N, Ghadessi M, Jenkins RB, Triche TJ, Malik R, Bedenis R, McGregor N, Ma T, Chen W, Han S, Jing X, Cao X, Wang X, Chandler B, Yan W, Siddiqui J, Kunju LP, Dhanasekaran SM, Pienta KJ, Feng FY, Chinnaiyan AM. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013 Nov;45(11):1392-8. doi: 10.1038/ng.2771.Epub 2013 Sep 29. PubMed PMID: 24076601; PubMed Central PMCID: PMC3812362.

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Project 2: Preclinical Evaluation and Clinical Development of Potent Small-Molecule Inhibitors of the MDM2-p53 Interaction as a New Therapy for the Treatment of Human Prostate Cancer

Co-Leader: Shaomeng Wang, Ph.D.going to a new website
Co-Leader: David C. Smith, M.D.going to a new website

The long-term transitional goal of this project is to develop a highly potent and promising small-molecule inhibitor of the MDM2-p53 interaction (hereafter referred to as MDM2 inhibitor) as a new therapy for the treatment of human prostate cancer.

Successfully carried out, this project will pave the way for the development of an entirely new class of non-toxic, molecularly targeted anti-cancer therapy, either alone or in combination with other therapies, for the treatment of advanced prostate cancer.

Specific Aims

1. Determination of the in vitro activity, specificity and molecular mechanism of action of our potent MDM2 inhibitors in a panel of prostate cancer cell lines and normal cells.

2. Determination of the in vivo antitumor activity and molecular mechanism of action of our potent MDM2 inhibitors in animal models of human prostate cancer and examination of any toxicity to animals.

3. Performance of a Phase II clinical trial of AT-201 in prostate cancer patients with androgen-independent disease.

Publications:

  1. Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol. 2009;49:223-41. PMCID: PMC2676449.

  2. Shangary S, Wang S. Targeting the MDM2-p53 interaction for cancer therapy. Clin Cancer Res. 2008 Sep 1;14(17):5318-24. PMCID: PMC2676446.

  3. Yu S, Qin D, Shangary S, Chen J, Wang G, Ding K, McEachern D, Qiu S, Nikolovska-Coleska Z, Miller R, Kang S, Yang D, Wang S. Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem. 2009 Dec 24;52(24):7970-3. PMCID : PMC2795799.

  4. Zhao Y, Liu L, Sun W, Lu J, McEachern D, Li X, Yu S, Bernard D, Ochsenbein P, Ferey V, Carry JC, Deschamps JR, Sun D, Wang S. Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors. J Am Chem Soc. 2013 May 15;135(19):7223-34. doi: 10.1021/ja3125417. Epub 2013 May 3. PubMed PMID: 23641733; PMCID: PMC3806051.

  5. Zhao Y, Yu S, Sun W, Liu L, Lu J, McEachern D, Shargary S, Bernard D, Li X, Zhao T, Zou P, Sun D, Wang S. A Potent Small-Molecule Inhibitor of the MDM2-p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice. J Med Chem. 2013 Jun 20. [Epub ahead of print] PubMed PMID: 23786219.

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Project 3: Defining Genetic Risk Factors for Brothers of Men with Prostate Cancer

Co-Leader: Kathleen A. Cooney, M.D.going to a new website
Co-Leader: Julie A. Douglas, Ph.D.going to a new website

This project is a continuation of our previous SPORE project in which we hypothesized that prostate cancer susceptibility loci with modest penetrance could be identified and characterized using family-based association studies. In this project, we plan to test the hypothesis that common nonsynonymous single nucleotide polymorphisms (nsSNPs) in BRCA1 and other candidate genes are associated with prostate cancer.

Specific Aims

1. Develop our new, formal collaboration with the SPORE program at Johns Hopkins University (JHU) to follow-up and generalize significant prostate cancer associations, including our previously reported prostate cancer association with BRCA1 Gln356Arg.

2. Complete a replication-based, genome-wide association study of early-onset and familial prostate cancer using more than 11,500 nonsynonymous single nucleotide polymorphisms (nsSNPs) that cover approximately 6,500 known human genes, including a disproportionate number in cancer-related pathways.

Major Publications

  1. Ewing CM, Ray AM, Lange EM, Zuhlke KA, Robbins CM, Tembe WD, Wiley KE, Isaacs SD, Johng D, Wang Y, Bizon C, Yan G, Gielzak M, Partin AW, Shanmugam V, Izatt T, Sinari S, Craig DW, Zheng SL, Walsh PC, Montie JE, Xu J, Carpten JD, Isaacs WB, Cooney KA. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med. 366(2):141-9, 2012. PMID:22236224. PMCID: PMC3779870.

  2. Zuhlke KA, Johnson AM, Okoth LA, Stoffel EM, Robbins CM, Tembe WA, Salinas CA,Zheng SL, Xu J, Carpten JD, Lange EM, Isaacs WB, Cooney KA. Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer. Fam Cancer. 2012 Dec;11(4):595-600. doi: 10.1007/s10689-012-9555-1. PubMed PMID: 22864661; PubMed Central PMCID: PMC3485445.

  3. Raymond VM, Mukherjee B, Wang F, Huang SC, Stoffel EM, Kastrinos F, Syngal S,Cooney KA, Gruber SB. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013 May 10;31(14):1713-8. doi: 10.1200/JCO.2012.44.1238.Epub 2013 Mar 25. PubMed PMID: 23530095; PMCID: PMC3641694.

  4. Xu J, Lange EM, Lu L, Zheng SL, Wang Z, Thibodeau SN, Cannon-Albright LA, Teerlink CC, Camp NJ, Johnson AM, Zuhlke KA, Stanford JL, Ostrander EA, Wiley KE,Isaacs SD, Walsh PC, Maier C, Luedeke M, Vogel W, Schleutker J, Wahlfors T,Tammela T, Schaid D, McDonnell SK, DeRycke MS, Cancel-Tassin G, Cussenot O, Wiklund F, Gr´┐Żnberg H, Eeles R, Easton D, Kote-Jarai Z, Whittemore AS, Hsieh CL,Giles GG, Hopper JL, Severi G, Catalona WJ, Mandal D, Ledet E, Foulkes WD, HamelN, Mahle L, Moller P, Powell I, Bailey-Wilson JE, Carpten JD, Seminara D, Cooney KA, Isaacs WB; International Consortium for Prostate Cancer Genetics. HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum Genet. 2013 Jan;132(1):5-14.doi: 10.1007/s00439-012-1229-4. Epub 2012 Oct 12. PubMed PMID: 23064873; PMCID: PMC3535370.

  5. Schroeck FR, Zuhlke KA, Siddiqui J, Siddiqui R, Cooney KA, Wei JT. Testing for the recurrent HOXB13 G84E germline mutation in men with clinical indications for prostate biopsy. J Urol. 2013 Mar;189(3):849-53. doi: 10.1016/j.juro.2012.09.117. Epub 2012 Oct 2. PubMed PMID: 23036981.

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Recently Completed Project

Project 4: Inhibition of CCL2 to Treat Metastatic Prostate Cancer

Co-Leader: Kenneth J. Pienta, M.D.
Co-Leader: Maha Hussain, M.D.going to a new website

The central hypothesis of this project is that systemic inhibition of monocyte chemoattractant protein -1 (MCP-1; CCL2) will be an effective treatment for prostate cancer.

Specific Aims

1. Determine the signal transduction pathways by which CCL2 promotes prostate cancer cell survival.

2. Dissect the role of increased CCL2 expression on monocyte mobilization in response to prostate cancer. Specific Aim 3: Test the human antibody CNTO888 to CCL2 in patients with prostate cancer. These aims remain unchanged from the submission of the grant.

Recent Publications

  1. Zhang J, Patel L, Pienta KJ. Targeting chemokine (C-C motif) ligand 2 (CCL2) as an example of translation of cancer molecular biology to the clinic. Prog Mol Biol Transl Sci. 2010;95:31-53. doi: 10.1016/B978-0-12-385071-3.00003-4. Review. PubMed PMID: 21075328; PubMed Central PMCID: PMC3197817.

  2. Zhang J, Lu Y, Pienta KJ. Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth. J Natl Cancer Inst. 2010 Apr 21;102(8):522-8. doi: 10.1093/jnci/djq044. Epub 2010 Mar 16. Review. PubMed PMID: 20233997; PubMed Central PMCID: PMC2857800.

  3. Roca H, Varsos ZS, Pienta KJ. CCL2 is a negative regulator of AMP-activated protein kinase to sustain mTOR complex-1 activation, survivin expression, and cell survival in human prostate cancer PC3 cells. Neoplasia. 2009 Dec;11(12):1309-17. PubMed PMID: 20019839; PubMed Central PMCID: PMC2794512.

  4. Zhang J, Patel L, Pienta KJ. CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev. 2010 Feb;21(1):41-8. doi: 10.1016/j.cytogfr.2009.11.009. Epub 2009 Dec 14. Review. PubMed PMID: 20005149; PubMed Central PMCID: PMC2857769.

  5. Mizutani K, Sud S, McGregor NA, Martinovski G, Rice BT, Craig MJ, Varsos ZS, Roca H, Pienta KJ. The chemokine CCL2 increases prostate tumor growth and bone metastasis through macrophage and osteoclast recruitment. Neoplasia. 2009 Nov;11(11):1235-42. PubMed PMID: 19881959; PubMed Central PMCID: PMC2767225.

  6. Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009 Dec 4;284(49):34342-54. doi:10.1074/jbc.M109.042671. Epub 2009 Oct 15. PubMed PMID: 19833726; PubMed Central PMCID: PMC2797202.

 

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