The Role of MAP Kinase Pathway Activation in the Treatment of NRAS-Mutant and Therapy-Resistant BRAF-Mutant Melanoma
Abstract
Melanoma is a common, aggressive skin cancer that arises in part due to exposure to damaging ultraviolet (UV) radiation from sun exposure. When melanoma spreads beyond the skin we call this metastatic melanoma, and more than 7,000 people die each year in the United States from this disease. Despite advances in the treatment of melanoma, including new therapeutics that work directly on the melanoma cancer cells and others that work to activate the body s immune system, most patients with metastatic melanoma will die of their disease. Retrospective studies have shown an increased incidence of melanoma in military personnel likely due to service in high sun exposure regions. Consistent with the notion of UV exposure being an important factor, rates or melanoma are higher in the US Air Force than in other branches of the military. Curing cancer remains an elusive goal; nonetheless, for certain types of cancers where combination treatments are curative, we know that we need more than one therapy, and the therapies must be different enough that cancers cannot create simple escape mechanisms. In this case of melanoma, we have been unable to find such treatments. Certain types of melanomas bear genetic mutations that turn ON cancer growth pathways. Moreover, drugs that turn OFF these pathways work very well, but escape mechanisms then prevent these drugs from curing patients. We call this treatment resistance. We have recently discovered a new way to think about this problem. Specifically, we have found as melanoma cells try to escape the drugs, they turn ON the growth pathways even more. We discovered that this makes them highly sensitive to further activation of these pathways. This discovery leads us to believe that cycles of therapy where we first turn OFF the pathway, and then turn ON the pathway is likely to be highly effective. If we are right, it should be very difficult for tumors to find escape mechanisms or adaptations to avoid these two very different interventions. Imagine trying to slow down and speed up a car at the same time! We hope that such a strategy would lead to tumor eradication, and we are proposing to test this in human melanoma tumors growing in mice. What is the impact of this research? We hope for three impactful outcomes. (1) Establish a new paradigm of cycles of pathway inhibition and activation as a path to curing melanoma. (2) If successful, this research would lead to drug discovery efforts to find drugs that activate the pathway, as we proposed in our forthcoming publication. (3) The basic science approach we are taking, studying cancer evolution with DNA barcodes, would establish a way for melanoma scientists to understand whether therapeutic combinations can act to block the emergence of treatment resistance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210851
Entities
People
- William R Sellers
Organizations
- Broad Institute
- United States Army