Targeting Epigenetic Modifiers of Phenotype Switching in Targeted Therapy-Resistant Melanoma
Abstract
This proposal aims to address the Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) Focus Areas of Therapeutic Prevention of targeted therapy resistance and Minimal Residual Disease. Our lab developed an inhibitor, Corin, that shows promise in overcoming targeted therapy resistance of melanoma cells in the lab, and this proposal will determine if Corin can do the same in biopsy specimens from patients with melanoma. If so, we will use these patient samples to identify a panel of biomarkers and develop a test that can be used to predict response of melanoma patients to treatment with Corin and other targeted therapies. Success of our proposal will address the FY20 MRP Challenge Statement by determining why melanoma tumors become drug resistant and cause relapse, so that we can potentially use Corin to impede tumor progression. Significance: Melanoma, the fifth most common type of cancer in the United States, is the most aggressive form of skin cancer and caused an estimated 7,230 deaths in 2019. The US military engages in missions all over the world, including the Middle East, where the high ultraviolet (UV) index poses a higher risk for deployed US military personnel to develop melanoma. Although targeted therapies and immunotherapies for melanoma can help manage advanced stages of the disease, drug resistance remains a significant barrier to disease remission. Most patients undergoing targeted therapies usually develop resistance after 1 year, and the tumor cells that persist after drug exposure are known as minimal residual disease (MRD). Unique genetic mutations in tumors were once thought to cause this drug resistance, but recent research show that nongenetic changes in cancer cells explain their adaptability. This nonmutational mechanism of therapeutic resistance occurs due to cell plasticity, which is a cell’s ability to transform to a new cell identity that circumvents the drug-targeted pathway and enables therapeutic resistance. The reversible nature of cell plasticity presents a unique opportunity to prevent the emergence of targeted therapy resistance. Scientific Objective and Rationale: Our lab developed a small molecule inhibitor, Corin, that inhibits a complex known to induce cell plasticity that leads to targeted therapy resistance. In a series of prior studies, we found that Corin could kill cells in resistant melanomas in culture; moreover, in a preclinical study, Corin prevented resistant melanoma tumors from growing larger. In this proposal, we will use sophisticated genomic approaches to identify the therapeutic targets of Corin, such as genes and proteins, in melanoma cells derived from patients. These therapeutic targets will be further examined in patient biopsy specimens, to correlate its levels to patient response to targeted therapies. We expect to identify panels of biomarkers and develop a test that can be used to predict patient response to targeted therapy and sensitivity to Corin. Finally, we will establish a preclinical model of MRD, which will mimic a patient tumor undergoing targeted therapy that develops drug resistance. This MRD model will have an early shrink stage to correlate to a tumor’s initial response to therapy, and a progressive stage to correlate to development of drug resistance. We will use our MRD model to evaluate the therapeutic potential of Corin to prevent or reverse MRD. Impact and Research Application: MRD and drug resistance in melanoma tumors cause cancer relapse and disease progression, and our studies are likely to provide new therapeutic approaches to preventing relapse in these patients. The likely contribution of our study to advancing FY20 MRP Focus Areas is determining mechanistic targets of developing targeted therapy resistance. Additionally, our therapeutic Corin may potentially resensitize these mechanistic targets and thus prevent tumor progression in those at high risk of developing MRD of melanoma, especially for current Service Members
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110980
Entities
People
- Rhoda M Alani
Organizations
- Boston University Medical Campus
- United States Army