Targeting Autophagy via the Menin Protein to Inhibit Melanoma Metastasis
Abstract
Principal Investigator’s (PI’s) potential as a leader in melanoma: I am a tenured Associate Professor at Michigan. Most of my scientific work has focused on the sirtuins, proteins with roles in aging and disease. I am also a melanoma survivor. I was first diagnosed with invasive melanoma when I was 30 years old, and since then I have undergone more than 100 skin biopsies. Melanoma also claimed the life of my grandfather, who died of brain metastases. My father also suffered from metastatic melanoma, but was saved by immune checkpoint therapy. When my lab discovered by chance that a sirtuin we study, a molecule called SIRT5, was required for melanoma cell survival, I jumped at the opportunity to plunge deeply into melanoma research. We were fortunate to secure a Team Science Award from the Melanoma Research Alliance, and I am privileged now to serve as a member of their Grants Review Committee, where I have the opportunity to interact with, and learn from, top leaders in the melanoma field. Our first manuscript on SIRT5 in melanoma is currently under revision following positive reviews at JCI. We have begun to diversify our melanoma-related efforts and have identified a new major role for the Menin protein in melanoma, work that forms the basis for this DOD funding proposal. As a direct result of our interest in melanoma, I have assumed the leadership of the Cancer Biology graduate training program at Michigan. This program trains Ph.D. students in the science of cancer, who will ultimately make new discoveries to improve cancer treatment. This MCAA would allow my group to pursue our melanoma efforts in greater depth, and for me to steer our efforts increasingly toward addressing the clinical challenge of melanoma. I see our future studies focused on unravelling the biology of melanoma, particularly focused on links between metabolism and chromatin, with the goal of identifying “Achilles’ heels” that can be targeted with new medicines. Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) Focus Area/Challenge Statement: This proposal focuses on a new way to inhibit the stress response pathway called autophagy in melanoma, used by melanoma cells to resist treatment and facilitate metastasis. It is relevant to the FY20 MRP Focus Areas Minimal Residual Disease (micro-metastasis) and Therapeutic Prevention (recurrence). The proposal is responsive to the FY2020 MRP Challenge Statement to “prevent melanoma earlier in the disease cycle to prevent metastasis.” Scientific Objective/Rationale: Cutaneous melanoma remains by far the most lethal skin cancer. Unfortunately, despite new medicines, most individuals with advanced melanoma still die of their disease. In particular, although targeted therapies, such as BRAF and MEK inhibitors, work well at first for patients whose tumors have specific mutations, drug resistance rapidly develops in almost everyone. New treatment approaches are needed. Our studies have identified the Menin protein as a new candidate target in melanoma. Menin binds to many proteins in the cell to regulate their functions. Menin’s best-known role is to turn genes on and off. However, we have identified a new function for Menin in promoting a stress response pathway called autophagy. Autophagy is a process by which cells recycle their own components for fuel and building blocks. Autophagy helps melanoma cells resist targeted therapies. Our collaborators have made new drugs that block Menin action. These drugs are safe, and are now in human clinical trials for blood cancer. We find that many melanoma cells are remarkably sensitive to these Menin inhibitors. We propose that inhibiting Menin may be a new way to treat advanced melanoma. In this work, we will determine how Menin promotes autophagy at a detailed level, using advanced protein and gene expression techniques. We will also test Menin inhibitors in several different mouse melanoma models, both with and without standard targeted therapies for melanoma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110521
Entities
People
- David B. Lombard
Organizations
- United States Army
- University of Michigan