Abstract B25: Development of a nanoparticle containing the PI3K/mTOR dual Inhibitor, gedatolisib, for cancer therapy

Abstract

Abstract Gedatolisib, a PI3K/mTOR dual inhibitor delivered intravenously, is in early clinical trials in women with metastatic ER+ breast cancer. We reasoned that the therapeutic index could be further maximized by encapsulation of gedatolisib in nanoparticles (NP), thereby providing longer half-life, sustained release, blunting of Cmax and associated toxicity, asymmetric distribution to leaky tumor vasculature and the possibility of less frequent dosing. PF-07034663 is a polymeric NP encapsulating gedatolisib, targeted to prostate-specific membrane antigen (PSMA), a clinically validated tumor antigen expressed on prostate cancer cells and the neovasculature of some nonprostate solid tumors. Studies in mice, rats, and cynomolgus monkeys demonstrated that the terminal half-life of PF-07034663 following intravenous administration increased by ~1.5 fold and the Cmax of released gedatolisib from PF-07034663 decreased by ~75 fold compared to gedatolisib delivered by the same route. Gedatolisib released from PF-07034663 exhibited markedly enhanced intratumoral accumulation compared to gedatolisib (~40 fold), indicating enhanced tissue delivery and/or prolonged retention. In exploratory toxicology studies, PF-07034663 caused no hyper-insulinemic spike in rats, in contrast to gedatolisib. To evaluate the antitumor activity of PF-07034663, we performed tumor growth inhibition (TGI) studies in PSMA-positive C4-2 prostate and in PSMA-negative MDAMB361 ER+ breast and A549 lung xenograft tumor models. In the C4-2 model, PF-07034663 showed dose-dependent antitumor efficacy as a single agent, and, in combination with enzalutamide, exhibited enhanced activity leading to tumor regressions. PF 07034663 also exhibited prolonged, dose-dependent inhibition of phosphorylation of S6 (pS6) in the C4-2 model compared to gedatolisib. Interestingly, increased pharmacodynamics (PD) responses compared to gedatolisib were not restricted to PSMA-positive tumors. Moreover, TGI responses were increased in the PSMA-negative A549 lung cancer model, relative to those observed with gedatolisib. PF 07034663 treatment in spontaneous prostate tumors in PTENnullp53mut GEM mice and in subcutaneous allografts of these spontaneous tumors in wild-type mice showed that treatment of PF-07034663 caused similar pS6 inhibition in both models, suggesting that PD modulation is independent of tumor origin or milieu and is less likely due to altered enhanced permeability and retention (EPR) effect. Taken together, PF-07034663 exhibits potential for improved tolerability, sustained tumor PK, prolonged PD modulation, and less frequent dosing schedule compared to gedatolisib. These results support further exploration of gedatolisib in tumor-targeted or non-tumor-targeted nanoparticles in clinical trials as a promising vehicle for delivery of PI3K/mTOR inhibitors to advanced cancer patients. Citation Format: Lianglin Zhang, Gabriel Troche, Ravi Visswanathan, Wenhu Huang, Young-Ho Song, Mary E. Spilker, Zhenxiong Wang, Hui Wang, Anand Giddabasappa, Louise Cadzow, Susan Low, Greg Troiano, Jennifer Lafontaine, Valeria Fantin, Robert T. Abraham, Shubha Bagrodia. Development of a nanoparticle containing the PI3K/mTOR dual Inhibitor, gedatolisib, for cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B25.