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

Aviram Mizrachi, Yosi Shamay, Janki Shah, Samuel Brook, Joanne Soong, Vinagolu K. Rajasekhar, John L. Humm, John H. Healey, Simon N. Powell, José Baselga, Daniel A. Heller (), Adriana Haimovitz-Friedman () and Maurizio Scaltriti ()
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Aviram Mizrachi: Head and Neck Service, Memorial Sloan Kettering Cancer Center
Yosi Shamay: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center
Janki Shah: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center
Samuel Brook: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Joanne Soong: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Vinagolu K. Rajasekhar: Memorial Sloan Kettering Cancer Center
John L. Humm: Memorial Sloan Kettering Cancer Center
John H. Healey: Memorial Sloan Kettering Cancer Center
Simon N. Powell: Memorial Sloan Kettering Cancer Center
José Baselga: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Daniel A. Heller: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center
Adriana Haimovitz-Friedman: Memorial Sloan Kettering Cancer Center
Maurizio Scaltriti: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14292

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