Determining a Role for PP2A in the Development and Treatment of Endometriosis
Abstract
Endometriosis is a reproductive disorder affecting 5%-15% of women of reproductive age, caused by endometrial tissue aberrantly growing outside of the uterus. Despite the high prevalence and debilitating nature of this disease, the causes of endometriosis are still not well understood, and many women diagnosed with endometriosis have few therapeutic options. 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. Recent studies have suggested that the invasive phenotype of endometriosis shares similar mechanisms with tumor metastasis. In support of the link between endometriosis and cancer, recent genetic studies have identified cancer mutations present in endometriosis tissues. Researchers believe that there may be shared mechanisms in the development of endometriosis and cancer. One particular tumor suppressor, Protein Phosphatase 2A (PP2A), is frequently turned off in a wide range of human cancers, and has recently been found to be turned off, or mutated, in endometriosis. Based on this, we hypothesize that PP2A is also a key suppressor of endometriosis. PP2A is built through the assembly of a scaffolding A-subunit, a catalytic C-subunit, and one of four classes of regulatory B-subunits. Our lab has classified a class of small molecules, called Small Molecule Activators of PP2A (SMAPs), which take PP2A from an off state to an on state by stabilizing the fully assembled A/B/C complex. These drugs represent one of the first known and published examples of small molecules that turn on the brakes to kill cancer cells. An imbalance in estrogen and progesterone signaling contributes to endometriosis development. PP2A is known to regulate both signaling pathways. Here, we seek to understand if turning off PP2A, by mutation, leads to altered estrogen and progesterone signaling and ultimately endometriosis development. We will also explore the effects of turning on PP2A, by SMAPs, on estrogen and progesterone signaling and determine if SMAPs can stop the growth of endometriosis tissue, like how SMAPs can stop the growth of cancer cells. This proposal will test the contribution of PP2A mutations on endometriosis development for the first time. Additionally, this proposal will determine if small molecule activation of PP2Ais a new therapeutic strategy for endometriosis treatment. Combined, this proposal covers the Peer Reviewed Medical Research Program (PRMRP) Topic Area of Endometriosis and two key PRMRP Strategic Goals: epidemiology, where novel mouse models will be developed, and treatment, where we will explore if SMAPs are a novel fertility-sparing and non-surgical therapeutic for the treatment of endometriosis. Together, with the successful completion of this proposal, we hope to contribute to improving the treatment options and quality of life of patients suffering from endometriosis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310046
Entities
People
- Caitlin O Connor
Organizations
- United States Army
- University of Michigan