Abstract 5387: ONC201/TIC10 is effective as a monoagent and synergizes with chemotherapy to induce cell death in non-Hodgkin's lymphoma

Abstract

Abstract Outcome for non-Hodgkin's lymphoma (NHL) patients using conventional treatment standards remains unsatisfactory, particularly in advanced stage/ relapsed disease creating an imminent need for investigating novel treatment strategies. ONC201/TIC10 is a small molecule (Allen et al, 2013) that induces p53-independent cell death in tumor cells while sparing normal cells through inactivation of the prosurvival kinases Akt and ERK. ONC201 is currently entering Phase I/II clinical trials as a monoagent in adult advanced cancers. We have previously shown that ONC201 induces significant cytotoxicity in preclinical models of human lymphomas (Talekar et al, ASPHO 2014). Here, we show that ONC201 is not only effective as a monoagent across several NHL cell lines, but that it also synergizes with several chemotherapeutic agents to cooperatively induce cell death in vitro. We found that ONC201 induces significant apoptosis in a diverse panel of human NHL cell lines at low micromolar concentrations (1.3 to 5.06 uM). Increased surface TRAIL and surface DR5 expression was noted in a dose-dependent manner across representative cell lines. The increase in surface TRAIL correlated with increase in sub-G1 DNA content, which suggests that TRAIL may serve as a potential biomarker of response to ONC201. ONC201-induced apoptosis was inhibited using a pan-caspase inhibitor and was blocked by an anti-TRAIL antibody RIK-2, which indicate induction of TRAIL-dependent cell death. Western blot analysis of ONC201-treated NHL cells suggests ERK inhibition and Foxo3a activation as a potential mechanism of cytotoxicity via TRAIL induction. In agreement with this notion, we also observed upregulation of PARP & DR5 and caspase-3 activation in response to ONC201 treatment. We further found that ONC201 synergizes to potentiate cytotoxicity with several chemotherapeutic agents approved for NHL treatment, particularly anthracyclines (doxorubicin), nitrogen mustard (bendamustine), antimetabolite (cytarabine) and proteasome inhibitor (bortezomib) via cell viability experiments that were corroborated by apoptosis assays. Together these results suggest that ONC201 is a potent antitumor agent in NHL as monoagent and in combination with several approved therapies that may be explored in phase Ib/II trials. Citation Format: Mala Kiran Talekar, David Dicker, Joshua Allen, Wafik El-Deiry. ONC201/TIC10 is effective as a monoagent and synergizes with chemotherapy to induce cell death in non-Hodgkin's lymphoma. [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 5387. doi:10.1158/1538-7445.AM2015-5387