MOLECULAR ANALYSIS OF CARCINOGENESIS IN THE PROSTATE

Sloan-Kettering Institute For Cancer Res, New York NY

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Abstract

DESCRIPTION (provided by applicant): Morphologically similar prostate tumors presenting in any assigned stage may behave in different fashions, hampering our ability to predict clinical behavior. Thus, it is critical to characterize and validate biological markers of clinical predictive significance. In addition, clinical advances on prostate cancer also depend on the development of animal models paralleling the human disease. The transgenic models we have engineered and those proposed, targeting prostate specific functional inactivation of Pten, Rb or p53, will allow us to mechanistically test the working hypothesize that their inactivation plays a critical role in prostate cancer pathogenesis. Furthermore, work from our laboratory and others disclosed the clinical implications of detecting alterations of these genes in human prostate cancer. Due to their critical roles in proliferative and apoptotic programs, we are systematically analyzing these genes and their regulatory mechanisms in primary prostate tumors. The aims are: 1) To determine whether inactivation of Pten, Rb and p53 are required for prostate tumor development and progression by: 1A. Defining, in knock-out mice, the role of Pten in prostate cancer initiation, promotion and progression; 1B. Dissecting in the Pten+/- mouse the multistep process towards prostate cancer pathogenesis; 1C. Generating a mouse model of prostate cancer by conditional, prostate specific, Pten inactivation, 1D. identifying target genes and genetic events relevant for prostate tumorigenesis in genetically defined mouse models of prostate cancer. 2) To determine the predictive significance of PTEN, RB and p53 in human prostatic carcinoma by systematically characterizing mutations and aberrant patterns of expression affecting: 2A. PTEN; 2B. RB pathway (including cyclin D1-Cdk4- p16, as well as cyclin E-Cdk2-p27, and E2F proteins); 2C. p53 pathway (p21lVVAF1,Mdm2 and p14ARF). In the context of this project, hypothesis-generating clinical studies will provide the statistical construct to determine whether an association exists between clinical endpoints and molecular events. Identification of such alterations may serve as predictive molecular markers to stratify patients into specific protocols. 3) To establish a protocol for marker development and clinical implementation through a strategy based on trial methodology and guided by statistical rigor. Programmatic interactions include those with RP1, taking advantage of the tumor banks and clinical research databases for correlative studies; RP4, providing mechanistic insights for biological therapeutic targets; and most of the cores (ie, CF3 Animal Models, CF5 DNA Array, CF1 Pathology, CF2 Informatics.) The main goal of this project is to translate basic and clinical research findings into clinical studies.