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Bcl-2 family proteins are implicated in the initiation and progression of multiple malignancies. Furthermore, expression of these proteins is associated with resistance to various anti-neoplastic agents, suggesting that inhibitors of these proteins should have therapeutic benefit both in combination regimens and as monotherapy. We have previously characterized small cell lung cancer as a novel therapeutic opportunity for inhibitors of Bcl-2 family proteins. Here, we describe the SCLC preclinical activity of ABT-263, an orally bioavailable small molecule inhibitor of Bcl-2 family proteins that is currently in Phase I clinical trials. ABT-263 has a Ki of < 1 nM against Bcl-2, Bcl-XL, and Bcl-w but binds more weakly to other anti-apoptotic Bcl-2 proteins. We examined ABT-263 in a panel of human SCLC tumor lines and found a wide range of sensitivities both in vitro and in vivo. Sensitivity to ABT-263 correlates well with expression of the Bcl-2 family members targeted by this compound. When delivered at a dose of 100 mg/kg/day, p.o., q.d. x21, ABT-263 was highly efficacious in four xenograft models of SCLC with a significant number of durable complete tumor regressions observed in each case. Significant anti-tumor activity was observed in four additional SCLC models. The efficacy of ABT-263 was comparable or superior to the activity of numerous cytotoxic agents (anti-mitotics, platinating agents, topoisomerase inhibitors). Indeed, ABT-263 was able to regress 1 cc H146 tumors more effectively than a maximally tolerated dose of docetaxel. A single 100 mg/kg dose of ABT-263 induced a marked increase (~10 fold) in activated caspase-3 relative to vehicle controls (measured by immunohistochemistry). A major obstacle associated with chemotherapy for SCLC is robust drug resistance that frequently develops following initial rounds of therapy. ABT-263 elicited tumor regression in a model of SCLC selected for resistance to paclitaxel. Furthermore, ABT-263 caused significant tumor regression following only 5 days of therapy, even after six prior cycles of treatment. These results indicate that ABT-263 is a promising agent for evaluation in the treatment of small cell lung cancer.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA