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; Maurizio Scaltriti

doi:10.1038/ncomms14292

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, Maurizio Scaltriti

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

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.

Original language	English
Article number	14292
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14292
State	Published - 13 Feb 2017
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Mizrachi, A., Shamay, Y., Shah, J., Brook, S., Soong, J., Rajasekhar, V. K., Humm, J. L., Healey, J. H., Powell, S. N., Baselga, J., Heller, D. A., Haimovitz-Friedman, A., & Scaltriti, M. (2017). Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma. Nature Communications, 8, Article 14292. https://doi.org/10.1038/ncomms14292

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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.",

author = "Aviram Mizrachi and Yosi Shamay and Janki Shah and Samuel Brook and Joanne Soong and Rajasekhar, {Vinagolu K.} and Humm, {John L.} and Healey, {John H.} and Powell, {Simon N.} and Jos{\'e} Baselga and Heller, {Daniel A.} and Adriana Haimovitz-Friedman and Maurizio Scaltriti",

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AU - Mizrachi, Aviram

AU - Shamay, Yosi

AU - Shah, Janki

AU - Brook, Samuel

AU - Soong, Joanne

AU - Rajasekhar, Vinagolu K.

AU - Humm, John L.

AU - Healey, John H.

AU - Powell, Simon N.

AU - Baselga, José

AU - Heller, Daniel A.

AU - Haimovitz-Friedman, Adriana

AU - Scaltriti, Maurizio

PY - 2017/2/13

Y1 - 2017/2/13

N2 - 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.

AB - 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.

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

Abstract

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