Abstract 4122: Tumor-specific PI3K inhibition via nanoparticle targeted delivery in head and neck squamous cell carcinoma

Abstract

Abstract Purpose: PI3K-pathway activation is the second most common genetic abnormality occurring in head and neck squamous cell carcinoma (HNSCC). Mutation or amplification of PIK3CA, the gene coding for the p110α subunit of PI3K, occur in 34%-56% of HNSCC and there is evidence that targeting PI3Kα in these tumors can be radiosensitizing. Small molecule kinase inhibitors of PI3Kα are showing promising activity. However, the use of this molecule is limited by serious side effects such as hyperglycemia, diarrhea and rush. In this study we aimed to apply novel nanotechnology for targeted drug delivery via the cell adhesion molecule P-selectin, which was previously shown to be overexpressed in tumor microvasculature. Furthermore, P-selectin is up regulated following radiation therapy (RT), which could enhance drug delivery using targeted nanoparticles. Experimental design: We explored the efficacy and specificity of targeted delivery of BYL719, a potent alpha-specific PI3K inhibitor, using nanoparticles that selectively target P-selectin present in the tumor microvasculature in PIK3CA-mutated HNSCC. We compared the antitumor effects of nanoparticle delivery versus standard oral gavage with free drug in PIK3CA mutated HNSCC cell line- and patient-derived xenografts (PDXs). In addition, we compared blood glucose and insulin levels between standard BYL719 administration and nanoparticle drug delivery at different time points after treatment. Furthermore, we sought to evaluate the radiosensitizing properties of BYL719 when combined with fractionated RT of 5X4Gy. Results: P-selectin targeted delivery of 50 mg/kg/week BYL719 resulted in a significant tumor growth delay, which was comparable to the standard drug administration of 350 mg/kg/week (50 mg/kg/daily). While blood glucose and insulin levels were spiking after standard oral gavage of BYL719, these parameters were virtually unchanged upon nanoparticle administration of the drug. The radiosensitizing abilities of low-dose nanoparticle-linked BYL719 were comparable to the drug concentrations used in standard daily BYL719 administration. When given concomitantly with fractionated RT, both methods showed robust enhancement of radiotherapy response in all the models tested resulting in durable control of tumor growth. Conclusions: P-selectin targeted delivery of a PI3Kα inhibitor resulted in inhibition of the PI3K/Akt/mTOR pathway without affecting glucose or insulin levels. The magnitude of pathway inhibition was sufficient to radiosensitize several HNSCC animal models. This novel targeting strategy could be translated to the clinic to treat patients with PIK3CA activated and radioresistant HNSCC tumors sparing most of the systemic adverse effects of PI3K inhibition. Citation Format: Aviram Mizrachi, Yosi Shamay, Janki Shah, Samuel I. Brook, Joanne Soong, Vinagolu K. Rajasekhar, John L. Humm, Simon N. Powell, José Baselga, Daniel A. Heller, Adriana Haimovitz-Friedman, Maurizio Scaltriti. Tumor-specific PI3K inhibition via nanoparticle targeted delivery in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4122. doi:10.1158/1538-7445.AM2017-4122