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|Ref Type||Journal Article|
|Authors||Hudson K, Hancox UJ, Trigwell C, McEwen R, Polanska UM, Nikolaou M, Morentin Gutierrez P, Avivar-Valderas A, Delpuech O, Dudley P, Hanson L, Ellston R, Jones A, Cumberbatch M, Cosulich SC, Ward L, Cruzalegui F, Green S|
|Title||Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Kα 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 PI3Kα and PI3Kδ with selectivity versus PI3Kβ, PI3Kγ, 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-μmol/L GI50s). 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. Mol Cancer Ther; 15(5); 877-89. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|AZD8835||PIK3CA inhibitor 16 PIK3CD inhibitor 25||AZD8835 inhibits PIK3CA and PIK3CD, potentially resulting in decreased growth of PI3K-dependent tumors (PMID: 26839307).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA mutant||estrogen-receptor positive breast cancer||sensitive||AZD8835||Preclinical||Actionable||In a preclinical study, AZD8835 inhibited proliferation of estrogen receptor (ER)-positive breast cancer cells harboring PIK3CA mutations in culture and suppressed tumor growth in xenograft models (PMID: 26839307).||26839307|
|PIK3CA K111N||estrogen-receptor positive breast cancer||sensitive||AZD8835||Preclinical||Actionable||In a preclinical study, AZD8835 inhibited proliferation of estrogen receptor (ER)-positive breast cancer cells harboring PIK3CA K111N in culture and induced tumor regression in xenograft models (PMID: 26839307).||26839307|
|PIK3CA E545K||estrogen-receptor positive breast cancer||sensitive||AZD8835||Preclinical||Actionable||In a preclinical study, AZD8835 inhibited proliferation of estrogen receptor (ER)-positive breast cancer cells harboring PIK3CA E545K in culture and suppressed tumor growth in xenograft models (PMID: 26839307).||26839307|
|PIK3CA mutant||Advanced Solid Tumor||sensitive||AZD8835||Preclinical||Actionable||In a preclinical study, AZD8835 inhibited growth of a variety of advanced solid tumor models with Pik3ca mutations in culture (PMID: 26839307).||26839307|