Regulation of Myeloma Progression by Protein Citrullination
Abstract
The proposed research focuses on myeloma, one of the fiscal year 2018 (FY18) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas. Despite recent improvements in myeloma treatment, almost all patients experience disease relapse and progression. We have recently identified a group of proteins called peptidyl arginine deiminases (PADs) as a potential target for inhibiting myeloma progression. PADs modify other proteins by a process known as citrullination, which changes the other proteins in a way that impairs their function. PADs are produced by cancer cells and usually function inside the cell, although recent publications have reported that some PADs are also secreted outside the cell and can therefore affect proteins on the outside of nearby cells. We have demonstrated that myeloma cells produce and secrete PAD4, and we think that this secreted PAD4 may affect surrounding cells in the bone marrow (where myeloma cells typically live) in a way that weakens the immune system and allows myeloma cells to evade destruction by immune cells. Our idea, which has not been previously described, is that PAD4 secreted by myeloma cells modifies proteins on the surface of immune cells in the bone marrow and by doing so reduces the effectiveness of the anti-myeloma immune response. We will use laboratory models of myeloma to investigate changes in immune cells as a result of PAD4 and determine whether treatment with a medication that blocks PAD4 can delay progression of myeloma. We will also study blood and bone marrow samples from patients receiving treatment for myeloma to better understand the role of PAD4 in patients. If successful, our study will justify further investigation of PAD4 blockers for myeloma, including clinical trials in patients. Because patients with myeloma eventually develop disease that is resistant to all of our effective medications, new therapies are very much needed. The FY18 PRCRP Military Relevance Focus Area that this proposed study addresses is a gap in treatment of military members, Veterans, and their beneficiaries who have been diagnosed with myeloma. The Health and Medicine Division of the National Academy of Sciences, Engineering, and Medicine concluded in its 1994 report on Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam as well as in 1996, 1998, 2002, and 2004 updates, that there is evidence of an association between exposure to the herbicides used in Vietnam and the development of multiple myeloma. Veterans who served in Vietnam, or Korean demilitarized zone or another area where Agent Orange or other herbicides were sprayed may develop myeloma due to exposure to these agents. If successful, the current proposal will offer a novel approach to the treatment of myeloma and therefore improve the outcome of US military members and Veterans who suffer from this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910630
Entities
People
- Yulia Nefedova
Organizations
- United States Army
- Wistar Institute