Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3K alpha and PI3K delta, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers

摘要

The PIK3CA gene, encoding the p110 alpha catalytic unit of PI3K alpha, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3K alpha is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3K alpha and PI3K delta with selectivity versus PI3K beta, PI3K gamma, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor-positive (ER+) breast cancer cell lines BT474, MCF7, and T47D (sub-mu mol/L GI(50)s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER+ breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. (C) 2016 AACR.