Abstract 4475: In vitro efficacy profiling of ONC201 in cancer cells reveals sensitivity pattern that is consistent with ER stress response
Authors: Allen Joshua E. , Ishizawa Jo , El-Deiry Wafik S. , Andreeff Michael , Garnett Mathew , Benes Cyril 
Published: August 2015

Abstract
ONC201 is a small molecule with optimal preclinical characteristics that led to the initiation of several ongoing clinical trials in advanced cancers. The preclinical efficacy of this novel agent has been demonstrated in a broad range of solid and liquid tumors and appears independent of many oncogene mutations or resistance mechanisms. To better characterize the differential sensitivity of tumor cells to ONC201 we performed in vitro efficacy across a large panel of cancer cell lines (&gt;1,000 cell lines) representing a diverse landscape in addition to profiling in the NCI60 panel. These efforts included a dose range of up to 20uM and 48-72 hour time points. An interim analysis of 482 cancer cell lines revealed that among the 72 hour readouts, non-Hodgkin's lymphoma, leukemia, and multiple myeloma appear to be the most sensitive tumor types to ONC201 among the available dataset. Similar results were obtained from cell viability assays at 48 hours post-treatment, revealing a multiple myeloma cell line as the most responsive at this earlier time point. Among solid tumors, glioblastoma multiforme (GBM) was among the most sensitive tumor types. This result along with available ONC201 preclinical data supports further investigation of GBM, which is an ER-stress sensitive tumor type that has not been addressed due to blood-brain barrier limitations that do not impede ONC201.
Recent mechanistic studies have implicated the ER stress response in the early stage mechanism of ONC201 that triggers its downstream antitumor effects. This mechanism is consistent with the in vitro efficacy profiling that point to non-Hodgkin's lymphoma and multiple myeloma as sensitive outliers, which are both ER stress-sensitive tumor types and approved indications for proteasome inhibitors. The switch from the adaptive to the maladaptive ER stress response is thought to be a function of time and severity of the stress. In accordance with this model, the kinetics of ONC201-induced cytotoxic are more rapid in non-Hodgkin's lymphoma, leuekemia, and multiple myeloma relative to other tumor types.
These interim sensitivity profile results support the involvement of the ER stress response in the mechanism of action of ONC201 that explains its kinetics of response. Furthermore, these results bode well for the active clinical trials that are assessing the antitumor activity of ONC201 in ER stress-sensitive tumors. Ongoing studies continuing to complete the in vitro assessment of the cancer cell lines panel and conduct genetic correlations to derive biomarkers or confirm its mutation-agnostic profile.
Citation Format: Joshua E. Allen, Jo Ishizawa, Wafik S. El-Deiry, Michael Andreeff, Mathew Garnett, Cyril Benes. In vitro efficacy profiling of ONC201 in cancer cells reveals sensitivity pattern that is consistent with ER stress response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4475. doi:10.1158/1538-7445.AM2015-4475