Abstract 551: MDM2 inhibition in combination with imipridone ONC201 treatment as a synergistic combination in solid tumors
Authors: George Andrew , Sahin Ilyas , Zhang Shengliang , Schwermann Maximilian , Di Cristofano Francesca , DeGeorge Charlotte , El-Deiry Wafik S. 
Published: June 2023

Abstract
Mouse double minute 2 homolog (MDM2) has emerged as a target of increasing interest in recent years following its initial identification as an oncogene and subsequent identification as an often-amplified marker of tumor aggressiveness across several cancer types, including breast cancer and several soft tissue and osteo-sarcomas. MDM2 is best characterized as a p53-targeting E3-ubiquitin ligase, and significant efforts have been made to develop inhibitors that function to block MDM2-p53 binding and subsequent ubiquitination, thereby stabilizing p53. One such inhibitor, milademetan (RAIN-32), for instance has progressed to the clinic and has completed phase I and II trials both alone and as a combination agent in several hematological malignancies and solid tumors, and a phase III trial (MANTRA, NCT04979442) is currently underway. Given the role of p53 in contributing to transcriptional activation of MDM2, however, such inhibitors of MDM2-p53WT interaction serve to increase cellular levels of MDM2, a result which we have confirmed across several MDM2-p53 inhibitors and cell lines. Non-p53 mediated roles of MDM2 have become of increasing interest in recent years, and we have previously reported on MDM2 mediated immune effects. Further, studies of immune checkpoint blockade driven hyperprogressive disease in clinical cases have preliminarily identified MDM2 amplification as a potential predictor. Indeed, use of small-molecule degrader SP-141 which drives MDM2 autoubiquitination and subsequent proteolysis in both p53WT and p53-/- HCT116 cell lines demonstrates a remarkably similar IC50 (523 and 505 nM, respectively, at 72h) that suggests the importance of non-p53-dependent MDM2 pathways. ONC201 is a small molecule imipridone that is currently in clinical trials for brain cancers and a variety of other tumor types. Initially identified for its role in driving the TRAIL-pathway and integrated stress response (ISR), we recently identified an additional effect of ONC201 in demonstrably reducing detectable MDM2 levels in cell lines upon treatment. Preliminary investigation into this effect suggests synergism in combination with milademetan treatment, with the MDM2-p53 inhibition driven increase in MDM2 levels being abolished upon cotreatment of ONC201 and milademetan. Further exploration of this combination is underway, and may serve as a novel translatable therapeutic approach, particularly in combination with checkpoint blockade.
Citation Format: Andrew George, Ilyas Sahin, Shengliang Zhang, Maximilian Schwermann, Francesca Di Cristofano, Charlotte DeGeorge, Wafik S. El-Deiry. MDM2 inhibition in combination with imipridone ONC201 treatment as a synergistic combination in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 551.