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PMID: 28194032 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma.

Nature communications ·Vol. 8 ·2017-00-13 ·Pages 14292

Mizrachi A, Shamay Y, Shah J, Brook S, Soong J, Rajasekhar VK, Humm JL, Healey JH, Powell SN, Baselga J, Heller DA, Haimovitz-Friedman A, Scaltriti M

Abstract

Alterations in PIK3CA, the gene encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3Kα), are frequent in head and neck squamous cell carcinomas. Inhibitors of PI3Kα show promising activity in various cancer types, but their use is curtailed by dose-limiting side effects such as hyperglycaemia. In the present study, we explore the efficacy, specificity and safety of the targeted delivery of BYL719, a PI3Kα inhibitor currently in clinical development in solid tumours. By encapsulating BYL719 into P-selectin-targeted nanoparticles, we achieve specific accumulation of BYL719 in the tumour milieu. This results in tumour growth inhibition and radiosensitization despite the use of a sevenfold lower dose of BYL719 compared with oral administration. Furthermore, the nanoparticles abrogate acute and chronic metabolic side effects normally observed after BYL719 treatment. These findings offer a novel strategy that could potentially enhance the efficacy of PI3Kα inhibitors while mitigating dose-limiting toxicity in patients with head and neck squamous cell carcinomas.

MeSH Terms
Animals Carcinoma, Squamous Cell/drug therapy,metabolism Cell Line, Tumor Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors,metabolism Drug Delivery Systems/methods Head and Neck Neoplasms/drug therapy,metabolism Humans Mice, Nude Microscopy, Electron, Scanning Nanoparticles/chemistry,ultrastructure Protein Kinase Inhibitors/administration & dosage,chemistry,pharmacology Thiazoles/administration & dosage,chemistry,pharmacology Treatment Outcome Xenograft Model Antitumor Assays
Chemicals
Protein Kinase Inhibitors Thiazoles Alpelisib Class I Phosphatidylinositol 3-Kinases PIK3CA protein, human
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Mizrachi Aviram
Head and Neck Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. | Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Shamay Yosi
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Shah Janki
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Brook Samuel
Human Oncology &Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Soong Joanne
Human Oncology &Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Rajasekhar Vinagolu K
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Humm John L
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Healey John H
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Powell Simon N
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Baselga José
Human Oncology &Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. | Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Heller Daniel A
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. | Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA.
Haimovitz-Friedman Adriana
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Scaltriti Maurizio
Human Oncology &Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. | Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms14292
Published
2017-00-13
Epub
2017-00-13
Pages
14292
Language
English
Region
England
NLM ID
101528555
PMCID
PMC5316830
Subset
IM
Grants
NICHD NIH HHS · DP2 HD075698 · United States
NCI NIH HHS · P30 CA008748 · United States
External Links
PubMed source DOI: 10.1038/ncomms14292 PMC Full Text View journal details
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