AD Award Number : DAMD 1798-1-8521 TITLE : Centrosome Defects , Genetic Instability and Prostate Cancer

s Related to Prostate Cancer (33 during 2000-2002). ♦ Patents. ♦ 1. Cancer Detection by Centrosome Abnormality (U.S. #5,972,626). ♦ 2. Centrosome Defects in precancerous lesions as tools for tumor diagnostics, prognostics and treatment (U.S. patent pending; UMass docket#:UMMC 02-33) ♦ 3. Novel centrosome proteins involved in cytokinesis and cell cycle control (U.S. patent pending; UMass docket #: UMMC 02-23) ♦ 4. Centrosome protein-induced cell cycle arrest as a potential cancer therapeutic (patent pending) ♦ Clinical Translational Research. We ultimately hope to develop prognostic tests and therapeutics for detection of centrosome defects in PIN and for the treatment of aggressive prostate cancer, respectively. ♦ Development of Permanent Cell Lines (Prostate Tumor and Nontumor Lines): 1. HA-pericentrin-expressing cells (tetracycline-inducible) to study oncogenic effect of pericentrin. We constructed 3 tumor lines (PC-3, DU-145, LN-Cap). 2. GFP-histone fH2B)-expressing cells for studying segregation of GFP-labeled chromosomes in living cells: PC-3, DU-145, LN-Cap. Stephen Doxsey (DAMD17-98-1-8521) Funding obtained based on tliis work. 1. Received funding from Department of Defense for a postdwtoral fellow in Doxsey laboratory to work on centrosomes in breast cancer (Aruna Purohit, $50K, 1 year, 2000, Concept Award, BC996519). 2. Received funding from Department of Defense for a postdoctoral fellow in Doxsey laboratory to work on centrosomes in breast cancer (Keith Mikule, $17IK, 3 years, 2003-2006, Postdoctoral Traineeship Award, 80)21594). 3. Received funding from Department of Defense for a predoctoral fellow in Doxsey laboratory to work on centrosomes in breast cancer (Agata Jurczyk, $90K, 3 years, 2003-2006, Predoctoral Traineeship Award, BC020172). 4. Received funding from The Hershey Family Foundation/Prostate Cancer Walk Committee to intitiate studies on "Differentiation Therapies Based on Inhibiting Centrosome Genes" (1 year, $30K, 2003). Promotions obtained based on research supported by this award. The P.I. (SJD) was promoted to Associate Professor (7/99) based in part on work accomplished in this proposal and is currently being promoted to Full Porfessor based in part on this work. Dr. Aruna Purohit was promoted to Instructor based on her work on prostate cancer (20(X)). Reviewer: Prostate Cancer Review Panel (1997-present) and Breast Cancer Review Panel (1999-present); 2002: ad hoc reviewer, NIH. REPORT BODY: CONCLUSION. We believe that our work on centrosome dysfunction will have a significant impact on our understanding of prostate cancer progression and etiology. It also has the potential to improve our ability to detect and treat the more aggressive and devastating forms of this disease. One compelling reason for this assertion is that our hypothesis examines a fundamentally different and unexplored mechanism for prostate cancer development and progression: that centrosome defects cause genetic instability and cytologic anaplasia, and thus underlie the genesis of malignant disease. For this reason, the reviewers of the original proposal described it as unique and highly innovative. Insights gained from this approach should yield novel information on cellular processes, structures (centrosomes) and molecules (pericentrin) that have the potential to serve as therapeutic targets and prognostic indicatore of malignant disease. The discovery that centrosome defects are present in precancerous lesions of the prostate and the identification of a tumor-specific centrosome abnormality indicates that centrosome defects may serve as prognostic indicators of malignant disease. The presence of centrosome defects at the earliest disease stages also suggests that centrosomes may play an active role in the tumorigenic process and thus, may serve as prime therapeutic targets. We hope to complete the analysis of PIN lesions to determine if centrosome defects at this stage serve as prognostic indicators of aggressive disease. Pericentrin may be a novel molecular target for prostate cancer therapeutics since artificial elevation of pericentrin in normal prostate cells induces a tumor-like phenotype and since pericentrin levels are sj^cifically elevated in tumors and precancerous lesions. Within the next year we will test whether pericentrin-expressing cells develop or exacerbate tumor formation in vivo. Other proteins identified in the siRNA screen of centrosome protein function may also serve as prime targets for cancer therapeutics. In conclusion, we have produced compelling data in support of our unique centrosome-based model for prostate cancer progression. We believe this research will provide novel and more discriminating tools for prostate cancer prognosis and treatment. 1 Stephen Doxsey (DAMD17-98-1-8521)