Abstract 393: Predictive biomarker evaluation and molecular differentiation for imipridones ONC201 and ONC206

Abstract

Abstract Imipridone ONC201 is a first-in-class dopamine receptor D2 (DRD2) antagonist and mitochondrial protease ClpP agonist that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a chemical derivative of ONC201 currently in Phase I trials for central nervous system tumors, is also a DRD2 and ClpP dual targeting imipridone with differentiated target engagement and nanomolar potency. We explored molecular differentiation and predictive biomarker studies for ONC201 and ONC206 using gene expression profiling, development of resistance clones and RNA-seq/proteomics in large cancer cell line panels including the 1000-cell line GDSC panel. Gene expression profiling revealed ONC206 and ONC201 induce partially overlapping signatures in U87 glioblastoma cells. Similarly, T98G glioblastoma cells with acquired resistance to ONC201 or ONC206 revealed partial cross resistance and combinatorial efficacy, supporting distinct functional effects. Next, we evaluated a curated 35-gene panel corroborated from prior literature on ONC201 including DRD2- (DRD2, DRD5, TH, EGFR), ClpP- (ClpP, NDUFS7, NDUFA12, SDHA, SDHB, POLD2, POLDIP2), epigenetic- (EZH2, EED, EZHIP, KDM1A, KDM3A, KDM4A, KDM6A, KDM6B), hypoxia- (HIF1, HIF2, HIF3, VHL, VEGFA, HES1, TGM2, CELF2, P4HA2, CEBPB) and downstream signaling-related (ATF3, ATF4, MYC, MYCN, GNA11, GNA15) genes as predictive biomarkers for ONC201/ONC206 efficacy (IC50, IC90, AUC and mRNA fold change) in the GDSC panel using CCLE RNA-seq data. Optimized thresholds for predictive power revealed that the top molecular correlatives prioritized for ONC201 (ClpP, TGM2, NDUFS7, EZH2, EGFR, POLD2, HIF2A, CEBPB, HES1) and ONC206 (ClpP, TGM2, NDUFS7, EZH2, EGFR, HIF1, VHL, ATF4, MYC, KDM6B) in GDSC partially overlap. Biomarker combinations with the prioritized markers improved predictive power compared to single markers. Dual (both markers must be co-expressed) or independent combinations involving EGFR, NDUFS7, EZH2 and ClpP were most predictive for ONC206 while those involving ClpP, EGFR and EZH2 were most predictive for ONC201. Results from GDSC for ONC201 were further confirmed using the PRISM dataset with RNA-seq and proteomics that revealed similar results. Hypoxic tumor cell cultures confirmed GDSC findings that elevated tumor cell hypoxia can impart ONC201 or ONC206 resistance. Thus, ONC206 is a distinct agent that may be uniquely poised to address tumors that are not addressed by or have developed acquired resistance to ONC201. Our results indicate that for accurate prediction of ONC201 and ONC206 clinical benefit, a curated combinatorial biomarker approach for each tumor type, using diverse detection approaches such as protein expression, genomics, and transcriptomics, may be used in ongoing clinical trials. Citation Format: Sara Morrow, Kirti Nath, Yiqun Zhang, Mathew J. Garnett, Ultan McDermott, Cyril H. Benes, Joel Basken, Wafik S. El-Deiry, Joshua E. Allen, Varun V. Prabhu. Predictive biomarker evaluation and molecular differentiation for imipridones ONC201 and ONC206 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 393.