Reference Detail

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 24 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 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 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 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 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