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Ref Type Journal Article
PMID (26839307)
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 Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 15 5 2016 May 877-89 Mol Cancer Ther
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AZD8835 AZD8835 7 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD8835 AZD-8835|AZD 8835 PIK3CA inhibitor 26 PIK3CD inhibitor 27 AZD8835 inhibits PIK3CA and PIK3CD, potentially resulting in decreased growth of PI3K-dependent tumors (PMID: 26839307, PMID: 32194423).
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 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
PIK3CA wild-type PTEN loss breast cancer resistant AZD8835 Preclinical Actionable In a preclinical study, human breast cancer cells with wild-type PIK3CA and loss of PTEN were resistant to growth inhibition by AZD8835 in culture (PMID: 26839307). 26839307
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