Dual Inhibition of MDM2 and MDM4 Enhances Treatment Response of p53 WT Tumors

Combining MDM2 inhibitor with CK1α degrading agents and/or MDM4 prevents or inhibits p53wt MCC tumor growth.

Therapeutics

Project Overview

The tumor suppressor gene p53 is estimated to be mutated or deleted in about half of all cancers while p53 pathway signaling is disrupted in the remaining half. In the patient population with p53 wildtype (p53^wt) tumors, reactivating p53 may restore p53’s anti-tumor growth properties.
Dana-Farber scientists have shown that combination treatment with an MDM2 with CK1α degrading agents and/or an MDM4 inhibitor synergistically inhibits or prevents p53^wt MCC tumor growth in Merkel cell carcinoma.
Dana-Farber Cancer Institute is interested in licensing as well as collaborations, strategic research agreements (SRAs), or clinical trials.

Technology

Merkel cell carcinoma (MCC) is one tumor type in which in the vast majority, approximately 80% of cases, p53^wt is present. MCC is an aggressive skin cancer, whose incidence has tripled in the last two decades in the US. Immunotherapy initially helps 50-70% of patients but acquired resistance and non-responders make up a substantial group of patients that need alternative treatment options.

The proteins MDM2, MDM4, and CK1α are all directly or indirectly involved with suppressing p53 activity, thereby promoting tumor growth. Dana-Farber researchers have shown that combining an MDM2 inhibitor with CK1α degrading agents and/or an MDM4 inhibitor is successful at synergistically inhibiting or preventing p53^wt MCC tumor growth in a xenograft mouse model.

The team’s data suggest that these novel combinations can be used for treating p53^wt MCCs. Since p53 suppression by MDM2, MDM4, and CK1α is not exclusive to MCC, the results support this treatment regime in other p53^wt tumors. The MDM2 inhibitor includes nutlin-3, idasanutlin, and HDM201. The CK1α degrading agent and/or an MDM4 inhibitor include lenalidomide and SC-24-UR99.

Further Details:

Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response, DeCaprio & Park et al. Proc Natl Acad Sci U S A. 2019, 116(3)

Benefits of the treatment:

Lower toxicity is also anticipated due to the lower doses of MDM2 allowed by the synergistic effect of these drugs.

The present invention improves and expands the treatment options for patients with p53^wt tumors, notably, both solid and hematological, including MCC.

Team Members: James A. DeCaprio, MD, Jingwei Cheng, PhD, Donglim Park, PhD

Applications

Novel therapy options for p53^wt tumors.
Novel therapy options for p53^wt MCC patients.

Opportunities

Dana-Farber Cancer Institute is interested in licensing as well as collaborations, SRAs, and clinical trials.

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