Predictive Biomarkers of Response to Bc1-2 Biomodulation by G3139 and Docetaxel in Hormone-Refractory Prostate Cancer
Abstract
The central hypothesis is that bcl-2 protein over expression confers intrinsic resistance to chemotherapy in patients with hormone- refractory prostate cancer (HRPC), therefore downegulation of bcl-2 protein by the antisense oligonucleotide directed to Bcl-2, G3139, will enhance the antitumor activity of docetaxel in patients HRPC. To address this hypothesis and determine the predictive biomarkers for response to this therapy a phase II clinical study of G3139 combined with docetaxel was initiated in men with HRPC. The specific aims of the current grant (PC010504) are to demonstrate that bcl-2 over expression in prostate cancer specimens, the degree of bcl-2 downregulation in normal peripheral blood mononuclear cells (MNCs), and the pharmacokinetic parameters of G3139 and docetaxel will predict prostate cancer responsiveness to G3139 and docetaxel. Preliminary Results: thirty-one patients have been entered on the clinical study. Original tumor specimens have been obtained in 30/31 patients and immunohistochemical Bcl-2, Bax, Bcl-X1 expression will be determined in year 2. The mean G3139 steady-state concentrations were 5.51 +/- 1.63 mug/ml with moderate interpatient variability whereas MNC Bcl-2 protein expression declined by a median of 58% following 5 days of G3139 therapy. In year 2 and 3 of the grant the predictive biomarker and pharmacokinetic relationships will be determined.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2003
- Accession Number
- ADA414467
Entities
People
- Anthony W. Tolcher