Molecular Mechanisms of Therapy-Related Myeloid Neoplasms
Abstract
We have made significant advances over the last several decades in treating patients with cancer and are able to cure or delay progression in patients using a combination of chemotherapy and radiation. While, for most patients, this leads to improved overall outcomes, for a small number, the chemo and radiation exposure can unfortunately cause new leukemias known as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). We believe that leukemogenic environmental exposures such as radiation or organic solvents cause disease through a similar mechanism. These treatment-related leukemias are particularly deadly and difficult to cure. It is believed that because these leukemias developed and evolved in the setting of therapy, they are inherently resistant to our standard treatments. We have undertaken a large-scale genome sequencing project focused on patients who have received chemotherapy or radiation and have developed a secondary leukemia to better understand the gene mutations and processes that lead to these leukemias (Aim 1). We will correlate the gene mutation results to patient exposures and other clinical characteristics, hoping to generate practice-changing knowledge. By understanding how leukemias evolve and develop in the setting of chemotherapy and how specific therapies promote their development, we hope to identify ways to prevent their emergence and better treat them when they do form. Our preliminary work has identified two new associations between mutations and chemotherapy exposure and we propose to study them further. First, we have observed an association between exposure to lenalidomide, a frequently used standard of care drug for multiple myeloma, and the development of a specific mutant subtype of leukemia. With a novel mouse model developed in the lab, we will dissect how these leukemias form and evolve in the setting of lenalidomide treatment (Aim 2). Using these mechanistic insights, we hope to identify alternative therapies that can decrease the risk of leukemia development. Second, we have identified mutations in a gene known as SRCAP that is found primarily in the blood of patients who have been exposed to chemotherapy but not in those who are therapy naive. We propose to study this gene in detail to better understand the changes that occur in blood cells that are exposed to chemotherapy and how mutations in SRCAP may promote the development of therapy-related leukemia (Aim 3). The overarching goal of this project is to better understand treatment-related leukemias so that we can intervene early to prevent their development and identify new therapies to help cure these deadly blood cancers. As a physician-scientist, my ultimate goal is to combine clinical observations and patient-derived data with rigorous basic science investigation to yield opportunities to impact patient care. My passion for investigative research is fundamentally dependent upon its power to generate a deeper understanding of human disease and ultimately improve the care for the patients I see in the clinic. I am particularly committed to defining the basic mechanisms and genomic alterations that promote the development and progression of hematologic malignancies with the hope that such insight will translate into new strategies to prevent and treat these devastating cancers. The Department of Defense Career Development Award will dramatically accelerate my ability to accomplish these goals by providing necessary funding and resources. The proposed research will deliver a deeper understanding of critical mechanisms in treatment-related leukemias. These experiments will define the genetic and environmental interactions that lead to the development of therapy-related leukemias and the proposed mechanistic studies are focused on identifying novel prevention and treatment strategies. All patients treated with chemotherapy or radiation for any cancer are at increased risk of developing a therapy-related leukemia an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210223
Entities
People
- Adam Sperling
Organizations
- United States Army