Targeting the Menin-MLL1 Interaction in Melanoma
Abstract
This application focuses on Fiscal Year 2017 (FY17) Peer Reviewed Cancer Research Program (PRCRP) Topic Area “Melanoma and other skin cancers.” Although treatments for melanoma have improved dramatically in recent years, the majority of patients with metastatic melanoma still succumb to this disease. Identification of new melanoma therapies is a significant unmet need in oncology, both for military personnel and for the general population. Our proposal addresses the FY17 PRCRP Military Relevance Focus Area “Gaps in … treatment.” Our work tests the ability of new drugs we have generated that bind to a cellular protein called Menin to block melanoma cell growth. Active duty military personnel are at increased risk for melanoma relative to the general population due to increased ultraviolet (UV) exposure secondary to the demands of military service, and potentially also due to inconsistent use of sunscreen and other means of UV protection. Thus, our work will have a “particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries.” Scientific Objective/Rationale: Cutaneous melanoma remains by far the most lethal skin cancer. Unfortunately, most individuals with advanced melanoma still die of their disease. New treatment approaches are needed. Targeting the chromatin of melanoma cells may provide a new therapeutic approach to benefit patients with advanced melanoma. Chromatin refers to DNA bound to different proteins in the nucleus of the cell. Chromatin regulates gene expression and other aspects of DNA biology. In prior work, we developed small molecules that bind to the chromatin protein Menin. In preclinical testing, these small molecules proved extremely effective against blood cancers, with minimal toxicity towards normal cell types and whole mice. They are expected to move to human clinical trials for blood cancer beginning in 2018. We now find that many melanoma cells are very sensitive to these small molecules. We propose that inhibiting Menin may represent a novel therapeutic approach to treat advanced melanoma. In this application, we propose to test the sensitivity of melanoma cell lines to Menin inhibitors, define the mechanism of how Menin function in melanoma cells through gene expression studies, and test the ability of Menin inhibitors to treat melanoma in animal models. If successful, our work will identify a new approach to melanoma treatment that may be rapidly translated into the clinic. Applicability: In 2017, an estimated 87,110 new melanoma diagnoses and 9,730 melanoma-related deaths will occur in the U.S. The incidence of this disease has been steadily rising. It is among the 10 most frequently diagnosed malignancies. Due to the relatively young age of many melanoma patients, melanoma ranks third overall among all cancers in terms of years of potential life lost. Unfortunately, melanoma is notoriously aggressive and resistant to conventional treatments, such as chemotherapy and radiation. Our work may provide a new therapeutic option for patients with advanced melanoma, whose cancers are not curable via surgery alone. Menin inhibitors may be particularly beneficial for the more than 50% of patients with metastatic melanoma who do not experience a long-term response to immune checkpoint inhibition, the current best therapy for advanced melanoma. Menin inhibitors are expected to move to clinical trials very soon. Thus, following the preclinical studies in this proposal in melanoma models, Menin inhibitors could advance to the clinic rapidly, to initiate trials in patients with advanced melanoma. Relevance to Active Duty Service Members: Exposure to UV radiation is the major environmental risk factor for melanoma development. Military personnel show up to a 62% greater melanoma risk relative to the general population, likely due to increased UV exposure, the major environmental risk factor for melanoma. The highes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810453
Entities
People
- David B. Lombard
Organizations
- United States Army
- University of Michigan