Bcl-2 Antisense Enhances Docetaxel in Refractory Disease

ANAHEIM, California—An investigational antisense oligonucleotide directed against bcl-2 appears to help overcome the resistance of hormone-refractory prostate cancer to docetaxel (Taxotere). The combination of bcl-2 antisense (G3139, Genasense) and docetaxel, therefore, may prove to be effective in this type of cancer, researchers from the University of Texas Health Science Center, San Antonio, said at the American Urological Society annual meeting (abstract 690).

The bcl-2 protein is part of a larger family of proteins that regulates apoptosis and prevents cell death. The expression of the bcl-2 protein is increased in both number and intensity in prostate cancers that are hormone insensitive, compared with hormone-sensitive tumors.

In experimental models of radiation and hormone therapy, the bcl-2 protein confers resistance to apoptosis. It was hypothesized, therefore, that the protein might confer resistance to both androgen ablation therapy and chemotherapy in a prostate cancer model.

Anthony W. Tolcher, MD, associate director of clinical research at the CTRC Institute for Drug Development, reported that in a xenograft mouse model of prostate cancer, G3139 did, indeed, enhance the antitumor activity of docetaxel. "In this model, 7 of 10 mice were actually cured with the combination vs docetaxel alone, in which 3 of 10 mice were cured," Dr. Tolcher said.

They then conducted a phase I-II study of 20 patients (18 evaluable) with hormone-refractory prostate cancer. Eight had prior chemotherapy (which included prior taxanes in several cases). The patients received G3139 (5 to 7 mg/kg/d) as a continuous IV infusion for 5 days by portable pump, followed by docetaxel (60 to 75 mg/m²) given over 1 hour, with cycles repeated every 3 weeks. The optimal dose was determined to be G3139 7 mg/kg/d and docetaxel 75 mg/m².

Generally, the treatment was very well tolerated. Hematologic toxicity occurred in only one patient. Several patients experienced diuresis, and a few developed the typical docetaxel effects (alopecia, nail bed changes, and peripheral neuropathy). Several patients developed low-grade fever during G3139 infusion.

Downregulation of bcl-2 Protein

Both flow cytometric and Western blot analyses indicated marked downregulation of bcl-2 protein by day 5 in peripheral blood mononuclear cells. The one tumor that was biopsied showed a 40% reduction in bcl-2 expression after treatment, Dr. Tolcher reported.

Durable PSA responses have been seen in about half of the taxane-naïve patients, he said, including a major reduction in PSA levels and major objective responses in liver and viscera.

Seven of 12 taxane-naïve patients had greater than a 50% fall in PSA levels, and two had a more than 80% fall. Objective response was noted in two of four taxane-naïve patients with measurable disease. "One of these patients had bulky lymphadenopathy, which was considerably smaller after treatment and remained quite small even after 6 months," he said.

Dr. Tolcher and his colleagues concluded that the combination of G3139 7 mg/kg for 5 days plus docetaxel 75 mg/m² decreased the expression of bcl-2 protein both in peripheral blood mononuclear cells and in the one tumor that was accessible for biopsy. "The combination is active, with encouraging PSA and objective responses," he said. "We are moving forward with a standard phase II program, and we will also be looking for biomarkers predictive of response."

The session moderator, John Trachtenberg, MD, of Princess Margaret Hospital, Toronto, commented: "After years of modifications of hormone therapy, it is wonderful finally to be looking at new treatments that offer the opportunity for real advances."