Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies forPIK3CA-Dependent Breast Cancers

Abstract

The PIK3CA gene, encoding the p110a catalytic unit of PI3Ka, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Ka 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 PI3Ka and PI3Kd with selectivity versus PI3Kb, PI3Kg, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor-positive (ER þ ) breast cancer cell lines BT474, MCF7, and T47D (submmol/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 þ 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. Mol Cancer Ther; 15(5); 877-89. Ó2016 AACR.

The PI3K Pathway in Human Disease

“…For example, the p110α/δ inhibitor copanlisib (BAY80-6946; Table S1), which has a half-life of only 0.7 hr after intravenous (IV) administration in mice, was far more effective in mice bearing BT474 breast cancer xenografts when administered intermittently (3 times per week) than when administered by continuous dosing (Liu et al, 2013). Similarly, intermittent dosing of the p110α/δ-selective inhibitor, AZD8835, was clearly superior to daily dosing of this drug in a preclinical breast cancer model (Hudson et al, 2016). A pharmacokinetic-pharmacodynamic model, based on measurements of caspase-3 cleavage, was used to derive simulations of apoptotic rates.…”

“…Intermittent dosing of either one or both combination partners may ameliorate toxicity and enhance therapeutic index. This concept was tested in a mouse breast xenograft model with combinations of the p110α/γ selective inhibitor, AZD8835, dosed intermittently, and partnered with either intermittently dosed fulvestrant, with continuously administered palbociclib (Hudson et al, 2016). These combinations produced robust tumor regressions; indeed, a triplet combination (AZD8835 plus fulvestrant plus palbociclib), with each drug delivered according to the above protocol, induced profound tumor regressions.…”

Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors

“…Due to the safety profile associated with continuous dosing of PI3Kα inhibitors, preclinical studies have experimented with intermittent dosing schedules. Intermittent high doses of the PI3Kα/β inhibitor AZD8835 effectively blocked pAKT, induced apoptosis, and induced regressions in breast cancer xenografts, and facilitated combinations with fulvestrant and palbociclib in vivo (37). Likewise, treatment of tumor-bearing mice with high doses of pictilisib every 3 days enabled it to be combined with a MEK inhibitor and blocked growth of xenografts with KRAS or BRAF and PTEN or PIK3CA alterations (38).…”

AZD8835 inhibits osteoclastogenesis and periodontitis‐induced alveolar bone loss in rats

“…AZD8835 is a novel dual PI3K inhibitor, with selectivity against PI3Kα and δ isoforms, which is currently in phase 1 clinical trials. AZD8835 selectively inhibits wild‐type and mutant forms of PI3Kα and delivers strong antitumor efficacy (Barlaam et al, ; Hudson et al, ; Maynard et al, ). However, to the best of our knowledge, there are no reports discussing the role of AZD8835 in bone metabolism and CP‐induced ABL in vivo and in vitro.…”