Identification and Therapeutic Targeting of Paracrine Senescence Factors in the Prostate Tumor Microenvironment
Annual rept. 1 Mar 2009-28 Feb 2010
FRED HUTCHINSON CANCER RESEARCH CENTER SEATTLE WA
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The Purpose of this proposal is to examine how senescence in the prostate may be caused by medical treatments for prostate cancer, and to identify senescence-associated factors which may mediate resistance of neoplastic epithelium. To date, our major findings present a mixed picture of chemotherapy-induced senescence. Senescence-associated Beta-galactosidase staining has not identified significant chemotherapy-induced senescence, but quantitation of gene expression changes reveal a pervasive pattern of senescence changes. Correlation of chronological aging and senescence is seen. Detailed investigations into a putative secreted marker of senescence, STC1, find significant decreases in cancer compared to benign prostate glands, establish STC1 secretion as a response to numerous microenvironmental stressors including chemotherapy, and find increased STC1 expression in human prostate tissue after neoadjuvant chemotherapy. Finally, abrogation of the senescence-associated IGF pathway is being tested in a clinical trial of neoadjuvant anti-IGF-1R antibody therapy with combined androgen deprivation prior to prostatectomy.
- Medicine and Medical Research