Abstract 1155: Potent anti-cancer effects of selective GPR132/G2A agonist imipridone ONC212 in leukemia and lymphoma
Authors: Prabhu Varun Vijay , Madhukar Neel , Tarapore Rohinton , Garnett Mathew , McDermott Ultan , Benes Cyril , Charter Neil , Deacon Sean , Oster Wolfgang , Andreeff Michael , Elemento Olivier , Stogniew Martin , Allen Joshua 
Published: July 2017

ONC201, founding member of the imipridone class of compounds, is a highly selective small molecule G protein-coupled receptor (GPCR) antagonist that is in Phase I/II advanced cancer clinical trials. In this study, we evaluated GPCR engagement and antitumor activity of ONC212, an imipridone that is a chemical analogue of ONC201.

Experimental GPCR profiling using the PathHunter® β-Arrestin assay, determined that ONC212 is a selective agonist of the orphan GPCR GPR132/G2A. Multidose validation confirmed nanomolar GPR132 agonist activity (EC50 ~400nM). GPR132 is a stress-inducible orphan GPCR that causes G2/M arrest. The tumor suppressive role of GPR132 has been demonstrated most notably in lymphoid leukemia. Gene expression analysis of samples in the Cancer Genome Atlas (TCGA) revealed GPR132 is expressed in a range of tumor types with highest expression in leukemia and lymphoma.

The in vitro efficacy of ONC212 was assessed in the Genomic of Drug Sensitivity in Cancer (GDSC) collection of cell lines (&gt;1,000 cell lines). Cell viability assays were performed at 72 hours post-treatment to generate dose responses curves at concentrations from 78nM up to 20μM. ONC212 was broadly efficacious across most solid tumors and hematological malignancies in the low nanomolar range. Ranking the sensitivity of cancer lines to ONC212 by tumor type revealed that leukemia and lymphoma are the most responsive tumor types based on completeness of response (area under the dose-response curve). Interestingly, we also observed that high expression of GPR132 significantly correlated with ONC212 efficacy in GDSC cell lines, suggesting the importance of GPR132 agonist activity for ONC212 efficacy.

ONC212 was tested in 62 human leukemia cell lines that included acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML) and hairy cell leukemia. ONC212 demonstrated broad spectrum anti-leukemic activity and was equally efficacious across all leukemia subtypes tested. Most cell lines (60/62) were responsive to ONC212 with GI50 ranging from &lt;78nM to 456nM. Within ALL, both B-cell and T-cell ALL were highly sensitive to ONC212. ONC212 reduced cell viability in AML independent of complex karyotypes and p53 mutations that are associated with poor clinical prognoses.

ONC212 was also tested in 58 lymphoma cell lines comprised of anaplastic large cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL), Follicular Lymphoma and Hodgkin’s lymphoma. ONC212 reduced cell viability in most cell lines (56/58) and was equally efficacious regardless of subtypes with GI50 ranging from &lt;78nM to 261nM.

Thus, GPR132 agonist ONC212 possesses robust anti-cancer activity in hematological malignancies irrespective of leukemia and lymphoma subtype and provides further validation of the anti-cancer efficacy of the novel imipridone class of small molecules.

Citation Format: Varun Vijay Prabhu, Neel Madhukar, Rohinton Tarapore, Mathew Garnett, Ultan McDermott, Cyril Benes, Neil Charter, Sean Deacon, Wolfgang Oster, Michael Andreeff, Olivier Elemento, Martin Stogniew, Joshua Allen. Potent anti-cancer effects of selective GPR132/G2A agonist imipridone ONC212 in leukemia and lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1155. doi:10.1158/1538-7445.AM2017-1155