Degrading a Transcriptional Regulator of Mitochondria to Overcome Therapeutic Resistance in Melanoma
Abstract
Scientific Objective and Rationale: Melanoma is the most lethal form of skin cancer, and while most people are cured by initial surgical resection of the tumor mass, 5-year survival rates precipitously drop from 93% to approximately 27% for patients whose melanoma has spread. Moreover, due to deployments to geographic areas with elevated sun exposure, U.S. military personnel are at increased risk of developing melanomas. Despite revolutionary advances in treatments for metastatic melanoma, including the development of targeted therapies against mutant BRAF kinase and immunotherapies such as immune checkpoint blockade, many metastatic melanomas are either intrinsically resistant or acquire resistance to these treatments, leading to tumor relapse. Thus, uncovering new vulnerabilities in melanoma that could help overcome resistance to existing therapies is critical. Mitochondria, the power plants of the cell that are responsible for generating energy, have emerged as key drivers of therapeutic resistance for both targeted and immune therapies, but there are no FDA-approved drugs that target mitochondrial function in cancer. Thus, identifying and validating targets that regulate mitochondria could lead to improved therapies for melanoma. ZBTB11 is a transcription factor that regulates the expression of mitochondrial genes, but its role in melanoma is not well studied. We hypothesize that by virtue of its role in regulating mitochondrial genes, ZBTB11 orchestrates a transcriptional program that promotes resistance to targeted and immune therapies and thus represents a critical vulnerability in therapy-refractory melanomas. Impact: Our overall goal is to generate proof-of-concept data validating ZBTB11 as a therapeutic target in melanoma, which could open new avenues of research for overcoming intrinsic or acquired resistance to existing therapies. We believe that this could represent a significant advance for the treatment of patients with therapy-refractory melanomas.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210841
Entities
People
- Eric Wang
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army