title: Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers.
abstract: 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.
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom. kevin.hudson@astrazeneca.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hudson
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Urs J
authors.initials: UJ
authors.lastname: Hancox
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Cath
authors.initials: C
authors.lastname: Trigwell
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: McEwen
authors.affiliation: AstraZeneca Pharmaceuticals, CRUK-CI Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Urszula M
authors.initials: UM
authors.lastname: Polanska
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Myria
authors.initials: M
authors.lastname: Nikolaou
authors.affiliation: AstraZeneca Pharmaceuticals, CRUK-CI Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Pablo
authors.initials: P
authors.lastname: Morentin Gutierrez
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Avivar-Valderas
authors.affiliation: AstraZeneca Pharmaceuticals, CRUK-CI Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Oona
authors.initials: O
authors.lastname: Delpuech
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Phillippa
authors.initials: P
authors.lastname: Dudley
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Hanson
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ellston
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Alys
authors.initials: A
authors.lastname: Jones
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Marie
authors.initials: M
authors.lastname: Cumberbatch
authors.affiliation: AstraZeneca Pharmaceuticals, CRUK-CI Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Sabina C
authors.initials: SC
authors.lastname: Cosulich
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Lara
authors.initials: L
authors.lastname: Ward
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruzalegui
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Macclesfield, Cheshire, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007527:Isoenzymes; D051379:Mice; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000609108:AZD8835; D000970:Antineoplastic Agents; D007527:Isoenzymes; D010069:Oxadiazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines