Activity of VERU-111, an novel oral α and β tubulin inhibitor, against paclitaxel sensitive and resistant prostate cancer.

Abstract

302 Background: Following proven efficiacy of docetaxel against hormone sensitive advanced prostate cancer (CHAARTED and STAMPEDE studies), the use of docetaxel for the treatment of hormone sensitive and castrate resistant metastatic prostate cancer has increased. Unfortunately, the utility of taxanes in prostate cancer has been limited because of the development of resistance, the need for IV infusion, and the associated treatment toxicity. VERU-111 is a highly orally available, novel α and β tubulin inhibitor, developed using a rationale design strategy to bind through hydrogen bonds to the α and β subunits of tubulin. VERU-111 inhibits tubulin polymerization and is not a substrate for multi-drug resistance proteins, a common mechanism for taxane resistance. Methods: In this study, dosing regimens of VERU-111 (oral) were tested in comparison with docetaxel (IV) and a vehicle (oral) in PC3 as well as in paclitaxel resistant PC3 (PC3-TXR). xenograft models. VERU-111 was evaluated at 3.3 mg/kg (5 days/week), 10 mg/kg (3 days/week), 15 mg/kg (2 days per week), 15 mg/kg (3 days per week) and 20 mg/kg (1 day/week). The animals were treated for 28 days and tumor volume and percentage size were calculated. Results: In the parental PC-3 model, animals treated with oral VERU-111, in all of the dose schemes tested, performed statistically indistinguishably from the IV docetaxel administration. In the PC3-TXR model, IV docetaxel had no impact on tumor growth whereas oral VERU-111 resulted in almost complete inhibition of tumor growth at 3.3 mg/kg (5 days/week) and 10 mg/kg (3 days/ week) as well as 20 mg/kg (1 day/week). In early toxicity studies, the animals treated with VERU-111 did not suffer any significant safety signals and gained weight during treatment. Conclusions: VERU-111 is a novel, oral α and β tubulin inhibitor that has drug characteristics making it an ideal candidate to be a therapeutic option for hormone sensitive and castrate resistant advanced prostate cancer. VERU-111 can be administered, with efficacy, as infrequent as once per week and will not require daily dosing. Additional toxicity studies are currently being performed with a Phase 1/2 study being planned to begin later this year.