Abstract 3919: GSK458, a novel oral dual PI3K/mTOR Inhibitor, is effective in preclinical model of T-cell lymphoma alone and in combination therapies

Abstract

Purpose: Despite T cell lymphoma (TCL) responses well at the initial chemotherapy, the outcome of TCL remains poor when it becomes systematic disease with refractory or relapse (r/r) after several cycle of treatment. Constitutively activated PI3K-mTOR pathway was found variety of cancers including TCL, and dual inhibition of PI3k-mTOR has been shown preclinically and clinically successful in B-cell lymphoma. However, the activity of dual inhibition of PI3k-mTOR in T-cell malignancies remain utterly unknown. GSK458 is a potent oral dual inhibitor of pan PI3K (α, β, γ and δ) and mTOR (mTOR1 and mTOR2). Preclinical study showed GSK458 had broad antitumor activity in vitro and in vivo. In 2016, phase I clinical trial of GSK458 was competed and the dosage was durable in multiple tumor types. Here we extensively characterized the activity and the mechanism of action of GSK458 in preclinical model of T-cell lymphoma alone and in combination therapies. Methods: This study included a panel of T cell lymphoma lines as well as primary samples derived from lymphoma patient, including J45 and SupT-1 are PTCL as T-cell lymphoblastic lymphoma; whereas MJ, HH and H9 are CTCL represented Mycosis fungoides (MF), aggressive leukemic MF and the most aggressive form of CTCL Sezary syndrome (SS) respectively. In vitro viability assay was performed as single agent of GSK458 and in combination with other drugs. Differences in cellular metabolic difference were examined by ATP levels, low mitochondria potential and glucose update utilizing Cell-Titer Glo assays, DiOC6 and 2-NDG flow analysis, respectively. Cellular apoptosis and cell cycle distribution were evaluated by Annexin V and propidium iodide staining followed by flow cytometry. PI3K and mTOR downstream pathway phosphorylation status were detected by flow cytometry. Apoptosis proteins were detected by western blot. The regulative T cells were evaluated by flow cytometry. Results: GSK458 had potent anti-tumor activity as single agent and potentiated the activity of chemotherapy or small inhibitors, such as doxorubicin, carboplatin, venetoclax, brentuximab, romdespsin and proteasome inhibitors in TCL pre-clinical models. GSK458 sufficiently blocked the downstream targets of PI3K-mTOR, such as phosphorylation status of Akt serine473 and threonine308; phosphorylation of mTOR and GSK3β. At metabolic level, GSK458 reduced ATP production, decrease glucose uptake, lowered mitochondrial membrane potential and triggered apoptosis in TCL. Moreover, GSK458 arrested the cell cycle at G1. In our study, we found after exposure to GSK458, the percentage of regulatory T cell among the total CD4+ T cells were decreased. Conclusion: Based on these preclinical results, GSK458 appeared as a novel and promising drug that is possible to develop clinical trial in T-cell lymphoma. (Supported by Roswell Park Cancer Institute Alliance Foundation Grant) Citation Format: Juan J. Gu, Lianjuan yang, Jing He, Weina Shen, Cory Mavis, Francisco Hernandez-Ilizaliturri. GSK458, a novel oral dual PI3K/mTOR Inhibitor, is effective in preclinical model of T-cell lymphoma alone and in combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3919.