131807-144

ONC201, a small molecule Foxo3a activator, activity against patient-derived glioblastoma tumor-initiating cells.

Category: 
Central Nervous System Tumors
Session Type and Session Title: 
This abstract will not be presented at the 2014 ASCO Annual Meeting but has been published in conjunction with the meeting.
Abstract Number: 
e13022
Citation: 
J Clin Oncol 32, 2014 (suppl; abstr e13022)
Author(s): 
Dan Zhao, Sudhandra Sundaram, Hiroaki Wakimoto, William T. Curry, Daniel P. Cahill, Tracy Batchelor, Keith Flaherty, Joshua Allen, Andrew S. Chi; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Oncoceutics, Inc, Hummelstown, PA

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract: 

Background: ONC201 is a novel small molecule that inactivates MEK and Akt to induce Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) tumor suppressor expression in a Foxo3a-dependent manner and is able to cross the blood-brain barrier. Previous studies have verified preclinical cytotoxic activity in numerous cancer models including glioma. We sought to determine activity of ONC201 against patient-derived glioma tumor initiating cell (TIC) models in vitro and in orthotopic xenograft. Methods: We tested 5 TIC lines derived using the neurosphere system from untreated (MGG4, MGG8, MGG18) and recurrent (MGG67R and MGG152) glioblastomas. Several lines are known to have variable sensitivity to secreted TRAIL, including one (MGG4) that was reported to be resistant to secreted TRAIL-mediated cell death. We performed cell viability assays using ONC201 and IC50 values were calculated. SCID mouse brains were stereotactically implanted with TICs and mice were treated with ONC201 by oral gavage for in vivo pharmacodynamic and survival experiments. Results: ONC201 potently inhibited in vitro cell proliferation of all 5 lines, with IC50 values of 433 nm (MGG18), 688 nm (MGG152), 1.09 um (MGG8), 1.46 um (MGG4) and 3.97 uM (MGG67R). Pharmacodynamic and survival studies in orthotopic xenograft-bearing mice are ongoing. Conclusions: ONC201 has potent anti-proliferative activity in multiple glioblastoma TIC lines in vitro and may be a promising agent for glioblastoma with the potential to overcome the limitations of recombinant TRAIL and available cancer therapies.