Therapeutic Reactivation of the PP2A Tumor Suppressor for Breast Cancer Treatment
Abstract
Breast cancer represents the most common cause of cancer and the second leading cause of death in females. Many advances have been made in regards to the treatment of breast cancer based on the identification and targeting of drivers of disease. Despite these advances, many women diagnosed with breast cancer lack effective treatment options and women diagnosed at later stages have poor survival rates. Moreover, aggressive disease is characterized by the development of drug resistance as well as metastasis. Discovering new clinical interventions and therapies is critical for both the health of those dedicated to protecting our country and to our population as a whole. Breast cancer develops and progresses because of increased activity in oncogenes, genes that drive cancer, and by decreased function in tumor suppressor genes, genes that halt cancer progression. One particular tumor suppressor, Protein Phosphatase 2A (PP2A), is frequently turned off in a wide range of human cancers, including in breast cancer. This key anti-cancer protein, PP2A, is built through the assembly of a scaffolding A-subunit, a catalytic C-subunit, and one of four classes of regulatory B-subunits. Although recent studies have halted cancer progression by reactivating PP2A using Food and Drug Administration (FDA)-approved anti-psychotic drugs, the side effects of this approach were extremely detrimental. Our lab has reengineered these molecules by removing the damaging properties and isolating those that activate PP2A to fight cancer. We have classified these small molecules as Small Molecule Activators of PP2A (SMAPs). These drugs represent one of the first known and published examples of small molecules that turn on the brakes to kill cancer cells. This is in stark contrast to the majority of current cancer drugs, which turn off the accelerators to treat cancer. The turning off of this key brake, PP2A, has been observed to play a role in many different subtypes of breast cancer including both ER/PR-positive, HER2-expressing and triple-negative breast cancer as well. In this grant application, led by Dr. Goutham Narla, a physician scientist with long-standing expertise in PP2A and the Division Chief of Genetic Medicine, and Dr. Sofia Merajver, a breast cancer oncologist and physician scientist who has led international efforts in the care of high-risk breast and ovarian cancer patients and has long-standing expertise in translational breast cancer research, we are seeking to define the depth and breadth of activity of these class of drugs for breast cancer treatment in a panel of unique and well characterized cell based and in vivo model systems. This approach will allow us to both identify breast cancer patients who are the most likely to respond to this new class of drugs but also equally importantly will validate predictive biomarkers for patients suffering from breast cancer who are unlikely to respond those sparing them from unnecessary treatment. Additionally, based upon this approach of activating the brakes to treat breast cancer, we will test rationally designed drug combinations including with FDA-approved drugs for breast cancer treatment to maximize the efficacy of our approach while always trying to find the least toxic most tolerable approaches for our patients. By understanding how this new class of treatments works mechanistically at the cellular level and through revealing their anticancer properties in patients with a particular genetic makeup, we hope to contribute to improving the treatment options and quality of life of patients suffering from breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010108
Entities
People
- Sofia D Merajver
Organizations
- United States Army
- University of Michigan