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.
Nat Commun. 2017 Feb 13;8:14292. doi: 10.1038/ncomms14292.
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.
PIK3CA 基因（编码磷脂酰肌醇 3-激酶（PI3Kα）的 p110α 亚基）的改变在头颈部鳞状细胞癌中很常见。PI3Kα 抑制剂在各种癌症类型中显示出有前景的活性，但由于高血糖等剂量限制的副作用，其使用受到限制。在本研究中，我们探索了目前正在开发的用于实体瘤的 PI3Kα 抑制剂 BYL719 的靶向递送的疗效、特异性和安全性。通过将 BYL719 包封到 P-选择素靶向纳米颗粒中，我们实现了 BYL719 在肿瘤微环境中的特异性积累。这导致肿瘤生长抑制和放射增敏，尽管与口服给药相比，BYL719 的剂量低了七倍。此外，纳米颗粒消除了在 BYL719 治疗后通常观察到的急性和慢性代谢副作用。这些发现提供了一种新策略，可能在增强头颈部鳞状细胞癌患者 PI3Kα 抑制剂疗效的同时减轻剂量限制毒性。
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