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

Author

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  • Aviram Mizrachi

    (Head and Neck Service, Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Present address: Department of Otorhinolaryngology Head and Neck Surgery, Rabin Medical Center, 39 Jabotinski St., Petah Tikva 49100, Israel)

  • 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
    Memorial Sloan Kettering Cancer Center)

  • Daniel A. Heller

    (Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

  • Adriana Haimovitz-Friedman

    (Memorial Sloan Kettering Cancer Center)

  • Maurizio Scaltriti

    (Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

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.

Suggested Citation

  • 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 Haimovit, 2017. "Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma," Nature Communications, Nature, vol. 8(1), pages 1-10, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14292
    DOI: 10.1038/ncomms14292
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    Cited by:

    1. Chen Chen & You Wu & Shih-Ting Wang & Naxhije Berisha & Mandana T. Manzari & Kristen Vogt & Oleg Gang & Daniel A. Heller, 2023. "Fragment-based drug nanoaggregation reveals drivers of self-assembly," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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