Targeting Beta-Arrestins in Myeloid Malignancies
Abstract
Primary myelofibrosis (PMF) is a disease that occurs when stem cells in the blood or hematopoietic stem cells proliferate in excess, leading to production of too many blood cells. Unfortunately, effective therapies for this disease are lacking, with the only curative therapy being hematopoietic stem cell transplant, a procedure that comes with significant risk of complications and potential death. This disease is also associated with significant co-morbidities and a risk of progression to acute leukemia. Most patients with myeloproliferative disorders will have mutations in their cancer cells (JAK2V617F or MPLW515L mutations) that drive uncontrolled cell signaling through a signaling pathway call the JAK/STAT pathway. Treatment options exist to target this abnormal signaling pathway, although they are not curative and do no work for everyone. G protein-coupled receptors (GPCRs) are a large family of receptors that sense molecules outside of the cell and activate signaling inside of the cell. They are involved in many different diseases and are the targets of more than 40% of medicines used to treat patients. Beta-arrestins are scaffolding proteins found inside of cells that regulate signaling through GPCRs and also mediate cell signaling in their own right. They have been implicated in the development of several cancers, including chronic myeloid leukemia, another myeloproliferative disorder of blood stem cells. Our group has also recently demonstrated that a specific isoform of beta-arrestin, beta-arrestin2 (beta-arr2), is necessary in order for primary myelofibrosis to develop and progress using murine disease models. A novel therapeutic agent called an aptamer chimera has been developed that specifically targets beta-arrestin2 in cancer cells. In our work, we hypothesize that inhibition of beta-arrestin2 will specifically disrupt abnormal orpathogenic signaling in myeloproliferative neoplasms and that inhibiting beta-arrestin-mediated signaling pathways will improve outcomes in this morbid disease. We aim to apply an aptamer targeting beta-arrestin2 to disease models of primary myelofibrosis alone or in combination with other commercially available compounds. We also aim to confirm that abnormal signaling through beta-arrestin2 contributes to the development of myelofibrosis and other myeloproliferative neoplasms in human disease using patient samples for this purpose. Dr. Rein is trained both as a physician and as a scientist, and her interest both clinically and from a science perspective, is myeloproliferative neoplasms or cancers. Her goal as a scientist is to learn how to ask important and relevant scientific questions and to determine how to approach these questions in a thoughtful and logical manner in a basic science laboratory. Her goal as a physician is to provide effective and compassionate care for her patients. As both a physician and a scientist, she is in the unique position of being able to ask the questions that will directly benefit patients and investigate these hypotheses in the lab. Her ultimate career goal is to advance the development of new therapeutics to benefit those patients for whom we currently lack effective therapies. The Department of Defense Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program Career Development Award will allow Dr. Rein the protected time she needs to continue to develop her skills as a basic scientist and to learn new techniques necessary for a career as a successful independent physician-scientist. Dr. Lefkowitz, the primary mentor, is an expert in the field of G protein-coupled receptor signaling and physiology and has had over 40 years of experience mentoring scientists and physician scientists. He has published extensively on beta-arrestins and also has experience in myeloproliferative neoplasms, making him an ideal mentor to advance Dr. Rein’s career. This research will investigate a novel therapeutic agent and other potentially synergistic therapeutics
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010705
Entities
People
- Lindsay Rein
Organizations
- Duke University
- United States Army