Predictive Biomarkers of Response to Bc1-2 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 (oblimersen), 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 oblimersen and docetaxel; and (3) whether the pharmacokinetic parameters of oblimersen and docetaxel are predictive of bcl-2 biomodualtion and antitumor activity, respectively. Oblimersen steady-state concentrations are a predictive determinant of PSA response to the combination of oblimersen and docetaxel in patients with hormone-refractory prostate cancer. Although the majority of patients had marked decrements in Bcl-2 protein expression in MNCs following treatment with oblimersen, there was no relationship between the decrement in bcl-2 expression in MNC and response to therapy or Oblimmersen Css. Bcl-2, Bax and Bcl-X expression in the patient's original tumor block specimens was not predictive of response to therapy with oblimersen and docetaxel. Oblimersen Css is a significant predictor of PSA response to therapy with this combination. Oblimersen at the current recommended dose of 7 mg/kg/day in solid tumor studies may provide inadequate Css for a significant proportion of patients treated that may lead to suboptimal effectiveness in some clinical studies.