Predictive Biomarkers of Response to Bcl-2 Biomodulation by G3139 and Docetaxel in Hormone-Refractory Prostate Cancer

摘要

The specific aims of this grant are to demonstrate (1) that bcl-2 overexpression in prostate cancer specimens is a predictive biomarker for enhanced responsiveness to G3139, and antisense oligonucleotide targeting Bcl-2, and docetaxel; (2) that the degree of bcl-2 downregulation in normal tissue surrogate (peripheral blood mononuclear cells MNC) will predict prostate cancer responsiveness to G3139 and docetaxel; and (3) whether the pharinacokinetic parameters of 63139 and docetaxel are predictive of bcl-2 biomodulation and antitumor activity, respectively. The mean G3139 steady-state concentrations (Css) was significantly higher in responding patients than in those patients who did not respond (6.2 +/- 0.4 versus 4.3 +/- 0.3 microg/mL, p = 0.015), with a longer, although not statistically significant, increase in median survival for patients with Css > 5 microg/mL (689 versus 595 days, P > 0.05). Bcl-2 levels in MNC, although decreased in the majority of patients after 5 days of G3139, were not predictive of clinical response. G3139 Cs5 is a predictive marker for response and optimal concentrations for G3139 may need to be targeted above 5 microg/mL. Immunohistochemistry for Bcl-2, BAX and Bcl-X(L) and the relationship to response and survival is continuing.