IGF-1Axis and Insulin Resistance in PCPT

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DESCRIPTION (provided by applicant): Recent laboratory and epidemiologic research has provided evidence that insulin-like growth factors are involved in prostate carcinogenesis. Several prospective population studies suggest that elevated levels of IGF-I and insulin resistance represent novel risk factors for subsequent prostate cancer, and results consistent with this conclusion have been obtained in animal models of prostate carcinogenesis. However, important gaps in knowledge remain, and this application seeks to address these in the context of the unique opportunities provided by the Prostate Cancer Prevention Trial. Research will be undertaken to (1) test whether baseline serum concentrations of serum analytes related to IGF physiology and/or insulin resistance and/or related genetic polymorphisms are associated with risk of prostate cancer in general or high-grade tumors in particular, (2) investigate whether finasteride affects these serum analytes, (3) determine if there are interactions between baseline levels of these serum analytes and the effect of finasteride on prostate cancer risk, and (3) investigate whether concentrations of these analytes are related to apoptosis rate or proliferation rate of at-risk normal prostate cells and/or neoplastic prostate cells. In addition, it will be possible to examine jointly the effects of obesity and IGF levels on risk, and to address the hypothesis that certain dietary risk factors or protective factors for prostate cancer act through mechanisms that involve IGF physiology and/or insulin resistance. The proposed studies involve laboratory measurements to be performed on the extensive serum and tissue banks assembled for PCPT participants, and analysis of these data in conjunction with the PCPT outcome data. The proposed research will provide new basic science information related to prostate carcinogenesis, and also may (1) be relevant to definition of subgroups of men for whom finasteride is particularly valuable as a chemoprevention strategy, (2) aid in defining novel, potentially modifiable risk factors for prostate cancer. The revised Project addresses all reviewer concerns, including that for new preliminary data supporting the tissue IGF signaling studies in collaboration with Core C.