Abstract LB-284: Combination of antiandrogens and PI3-kinase pathway inhibitors in a model of androgen-dependent prostate cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Prostate cancer is the third most common cause of cancer-related deaths in men and is most prevalent in developed countries. The androgen signaling pathway plays a critical role in the development and maintenance of the prostate gland and is hyper-activated in prostate cancer. Additionally, gain of function mutations in the PI3 kinase pathway is associated with progression of this disease. Using the prostate-specific Pten -deleted mouse model of cancer, we show that these two pathways are distinct for tumor growth and disease progression. Depletion of androgens by either surgical or chemical castration significantly inhibits tumor growth without altering the activation of Akt and mTOR. We demonstrate that inhibition of mTOR with ridaforolimus or inhibition of Akt with MK-2206, combined with androgen deprivation (bicalutamide), results in additive anti-tumor effects in vivo when compared to single agent treatment. In this model, we also demonstrate that Akt inhibition does not block mTOR kinase activation, and that inhibiting both Akt and mTOR kinases together significantly enhances anti-tumor efficacy. Our data suggest that the combination of an anti-androgen with an mTOR inhibitor and/or Akt inhibitor may be more effective than standard therapies in treating androgen-dependent prostate cancer patients with an activated PI3 kinase pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-284.