Milademetan Plus ONC201 Could Represent Synergistic Combination in MDM2-overexpressing Solid Tumors

Ilyas Sahin, MD

The addition of the small molecule imipridone ONC201 to the MDM2-p53 inhibitor milademetan (RAIN-32) could form a synergistic combination for the treatment of patients with solid tumors with MDM2 overexpression, according to Ilyas Sahin, MD.

Findings from a preclinical study presented at the 2023 AACR Annual Meeting showed that the combination had a greater effect on cell viability, resulted in stabilization of p53 in cell lines, and prevented additional MDM2 expression from p53 transcriptional activity compared with monotherapies.

“When you use these drugs together, [the] increase in MDM2 levels that is usually seen with MDM2-p53 inhibition was abolished,” Sahin said. “[These findings are] very promising and suggest that these 2 drugs can be used in future studies, especially for patients with cancer who have MDM2-overexpressed tumors.”

Cellular responses from a 48-hour western blot analysis demonstrated an enhanced stabilization of p53 with low-dose monotherapy and combination therapy with milademetan and ONC201. Additionally, investigators noted that higher-dose monotherapy and combination therapy demonstrated a decrease in inhibitory-phosphorylated FOXO3a and suppression of normal feedback expression of MDM2 in response to milademetan monotherapy in the combination.

In an interview with OncLive^®, Sahin, an assistant professor at the University of Florida College of Medicine, detailed the preclinical findings from the study and highlighted how these data could help inform future studies for the treatment of patients with MDM2-overexpressing solid tumors.

OncLive: Could you elaborate on the background and rationale for investigating the combination of milademetan and ONC201 in solid tumors?

Sahin: The study is from the lab [of Wafik El-Deiry, MD, PhD, FACP] at Brown University.

The study focused on potential combination treatment for solid tumors using [the] MDM2-p53 inhibitor milademetan and ONC201. MDM2 is a well-known oncogene that is often amplified in various cancer types, including breast cancer and sarcomas. For many years, researchers have been developing inhibitors to block this MDM2-p53 interaction, which leads to p53 degradation. Milademetan is one such inhibitor that has progressed to phase 3 trials for hematologic malignancies and solid tumors.

ONC201 is a small molecule imipridone that is also currently being studied for various tumor types, and [it was] initially identified for its role driving [the] TRAIL pathway and integrated stress response.

In this study, they combined these 2 drugs. When you use MDM2-p53 inhibitors [such as] milademetan, the problem is when these drugs inhibit this pathway, they increase levels of MDM2, which may not be ideal because there are some non–p53-mediated roles of MDM2. Recent studies, including one of my previous studies when I was at Brown, showed that MDM2-mediated effects [potentially] can be independent from the p53 pathway.

Also, MDM2 amplification has been shown [to] potentially be predictive for hyperprogressive disease [driven by] immunotherapy. They wanted to combine these drugs to see if ONC201 can inhibit MDM2 levels.

Could you expand on some of the key findings from this research?

In addition to [ONC201’s] known role [in driving the] TRAIL pathway, when they combined these 2 drugs [in this study], they showed that ONC201 can reduce the detectable MDM2 levels in cell lines after treatment. They also observed that when they combined these 2 drugs, there was a synergistic effect.

What future research could these findings inform?

This is a preclinical study that is promising. Further research is underway to explore this combination more in mice and hopefully in humans. If the research proves to be successful, this could lead to a novel translatable therapeutic approach for treatment especially for [patients with] MDM2-overexpressing tumors.

Also, the combination therapy may have potential when used in conjunction with checkpoint blockade. MDM2 might have a role [in] immunotherapy resistance; that's why this combination could potentially have some impact on immunotherapy.I'm hoping to see further studies confirm this combination is as promising as this study showed. [We also want to see] if it is safe in humans.

In many cancers, immunotherapy [is] getting FDA approvals [in the] neoadjuvant setting, adjuvant setting, [or] in combination with other drugs. That's why we are trying to find a way to overcome resistance to immunotherapy. That's why this combination has a potential role in overcoming immunotherapy resistance in future studies.

Immunotherapy resistance is an ongoing issue, and we are trying to find a way to overcome it. That's where MDM2 might have a potential role. I would ask my colleagues to watch for MDM2-related research in the [future].

Reference

George A, Sahin I, Zhang S, et al. MDM2 inhibition in combination with imipridone ONC201 treatment as a synergistic combination in solid tumors. Cancer Res. 2023;83(suppl 7):551. doi:10.1158/1538-7445.AM2023-551