Identification and Therapeutic Targeting of Paracrine Senescence Factors in the Prostate Tumor Microenvironment.

摘要

The goal of this proposal was to examine the induction of senescence by common effective treatments for prostate cancer, and to further identify and target senescence-associated factors which might mediate resistance to these therapies in the neoplastic epithelium. Senescence cell biomarkers (p16 and DcR2) were correlated with aging and prostate cancer. The senescence-associated factors GDF15 and STC1 were found to correlate with neoplasia, but not aging. Stressful environmental conditions leading to altered secretion of STC1 were defined, but multiple studies seeking to define the function of STC1 in the prostate were uniformly negative. A clinical trial testing the effects of neoadjuvant anti-IGF-1R (IMC-A12) treatment in combination with androgen deprivation was completed and a panel of serum biomarkers were evaluated. We find biomarker evidence for good on-target efficacy and an intriguing correlation of PSA response with A12-induced insulin resistance that is not fully accounted for by pre-treatment factors such as body mass index.