Dysregulation of Sphingolipid Metabolism and Actions in Tuberous Sclerosis Complex
Abstract
Tuberous sclerosis complex (TSC) is a rare genetic disease that causes benign tumors to grow in many different organs of the body. Although TSC tumors are not metastatic, these tumors can still cause a wide variety of clinical problems, some critical, when the growth is located in vital organs such as the brain, kidney, and lung. Currently, there is no cure for TSC, and treatment is largely devoted to surgical removal of tumors. Sometimes drugs such as rapamycin or related agents are used to keep tumors from growing. Unfortunately, the current available drugs at best only stop the tumor growth and do not make the tumors go away. As a result, the tumors enlarge further as soon as rapamycin is discontinued. In addition, long-term treatment with these drugs can lead to side effects such as diabetes. Moreover, in some cases, patients can develop resistance to the treatment. In other words, TSC is an incurable lifelong disease, and the current treatments available only affect disease progression. There is no cure. It is imperative to develop new therapeutic approaches that can not only eliminate, rather than merely block tumor growth, but also exert actions without major side effects. What are objectives of our research? The main objective is to understand why TSC tumor cells are not destroyed by rapamycin and to discover the molecular reason for tumor growth. Our preliminary studies have identified a previously unappreciated pathway involving cell lipids that might in part account for the growth in TSC tumor cells. To explore further whether our speculation is true, we plan to alter the expression of this pathway both in tissue culture and in animal models in which we can monitor the growth of the tumor cells. Our ultimate goal is to use this new understanding to discover a treatment that will completely kill the cells in the tumors and thereby achieve a cure. What type of patients will receive benefit from our research? There is no immediate benefit because these are animal studies. However, the discovery of molecular reasons for TSC tumor cell growth and how rapamycin affects this pathway may lead the availability of new safe and curative drugs. In addition, our research may uncover other pathways that play a role in the growth of other kinds of tumors that are not caused by TSC but involve similar pathways. What are potential risks? This is a preclinical study. It will not pose a risk to patients. What are the likely contributions of this proposed research project to advancing the field of TSC research and/or patient care? Our proposal addresses the basic inadequacy of current TSC therapy and, therefore, has the potential for a marked and fundamental long-term impact on treatment of patients with TSC. Importantly, by identifying the pathways that might be used by rapamycin and the ones that are activated when rapamycin stops working, new therapies distinct from rapamycin may be discovered that are more effective than this drug and that are, unlike rapamycin, curative. The projected timeline for having an immediate impact on patient care is 3-5 years. In summary, these preclinical studies described in our proposal provide the possibility of a major long-term breakthrough in treatment of TSC because FDA-approved drugs, fingolimod and rapamycin, will be tested.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010736
Entities
People
- Jane Yu
Organizations
- United States Army
- University of Cincinnati