title: Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma.
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.
authors.affiliation: 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.
authors.forename: Aviram
authors.initials: A
authors.lastname: Mizrachi
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Yosi
authors.initials: Y
authors.lastname: Shamay
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Janki
authors.initials: J
authors.lastname: Shah
authors.affiliation: Human Oncology &Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Brook
authors.affiliation: Human Oncology &Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Soong
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Vinagolu K
authors.initials: VK
authors.lastname: Rajasekhar
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Humm
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.affiliation: 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.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: 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.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Heller
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.affiliation: 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.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C585539:Alpelisib; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human