Repurposing MEK Inhibitors for Lymphatic Malformations
Abstract
Lymphatic vessels are located in most regions of the human body, and they perform several essential physiological functions. Lymphatic vessels transport immune cells, absorb dietary fats, and return fluid to the cardiovascular system. Lymphatic malformations (LMs) are diseases caused by the abnormal development of lymphatic vessels. These malformed lymphatic vessels do not work properly and can cause severe morbidity and mortality in patients. Current treatments for LMs include surgery, sclerotherapy, and sirolimus. However, these treatments are inadequate for many patients. Therefore, there is an urgent need for new treatments for LMs. We and others have recently identified genetic mutations in KRAS in LM patients. KRAS is a small G-protein that activates the RAF/MEK/ERK signaling pathway. The mechanism by which mutations in KRAS cause LMs is poorly understood. We have found that mice that express a mutant form of KRAS in their lymphatic vessels develop fewer lymphatic valves than control mice. Lymphatic valves prevent the backflow of lymph as it moves through the body, and lymphatic valve defects can cause life-threatening complications in patients. In this application, we will investigate the mechanisms by which KRAS affects the maintenance of lymphatic valves (Aim 1). We will also test the effect of an FDA-approved MEK inhibitor (trametinib) on aberrant lymphatic development in our clinically relevant LM mouse model (Aim 2). The short-term impact of our project is that it will provide key insights into the molecular mechanisms controlling lymphatic valve maintenance. Filling this gap in knowledge will provide a deeper understanding of the pathophysiology of LMs. We will also produce a novel LM mouse model as part of this project. Our animal model will allow us to answer fundamental questions regarding the biology of RAS pathway-induced LMs. Additionally, our animal model will open up the field to investigators that want study LMs, but do not have access to patients or patient samples. The long-term impact of our work is that it could lead to the repurposing of FDA-approved MEK inhibitors for a spectrum of LMs and enable a precision medicine approach for the treatment of these life-threatening diseases. Filling this unmet medical need could improve patient outcomes and help alleviate the stress experienced by civilians, military Service Members, and Veterans raising a child with a LM. Our project directly relates to the FY20 PRMRP Topic Area of Vascular Malformations and Area of Encouragement “Development of in vivo or in vitro models of vascular malformations for the purpose of identifying novel and/or innovative drug targets, screening existing drugs, and/or elucidating the pathogenesis of the disease”. This multiple Principal Investigator project was conceived jointly by two lymphatic researchers whose laboratories were created to improve outcomes for patients with LMs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110652
Entities
People
- Michael Dellinger
Organizations
- United States Army
- University of Texas Southwestern Medical Center