Targeting Folate-Dependent Metabolic Pathways for the Treatment of TSC
Abstract
Tuberous sclerosis complex (TSC) is a genetic disease in which tumors can develop in multiple organs. TSC is caused by a mutation in the TSC1 or TSC2 gene, leading to activation of the mammalian target of rapamycin complex 1 (mTORC1). Treatment with mTOR inhibitors shrinks tumors in TSC, but the tumor cells are not killed. Therefore, when treatment is discontinued, the tumors regrow. Hence, continuous therapy is needed. Treatments for TSC that kill the tumor cells, so-called cytotoxic agents, are not currently available and could have a major clinical impact in TSC. After treatment with a cytotoxic agent, tumor cells will regrow slowly or not regrow at all. This project is founded on a high-throughput drug-repurposing screen to identify potential new treatments for TSC. The majority of the drugs in the screen are already Food and Drug Administration (FDA)-approved, allowing them to be "repurposed" for the treatment of tumors in TSC. The lead compound that I will investigate in this project, methotrexate (MTX), is used to treat tumors and also benign diseases, including rheumatoid arthritis. MTX treatment limits the availability of nucleotides, which are basic elements of DNA and other molecules. I will also investigate compounds that are FDA-approved that act similarly to MTX. My project has three specific aims. In this project, I will test the hypothesis that treatments that disrupt cell division will selectively eliminate tumor cells with TSC2 mutations and mTORC1 hyperactivation, with no toxicity on normal cells. I have discovered that inhibiting key regulators of the cell cycle including limiting the availability of the basic elements of our DNA (nucleotides) trigger a strong and selective death of cells TSC gene mutations and hyperactive mTOR. I will investigate the metabolic impact of these therapies in cells and in mouse models of TSC. These drugs and chemical agents will provide tools to address key knowledge gaps regarding cell division under the cellular stress induced by mTOR activation. My career goals as a TSC researcher are to identify novel therapeutic strategies and their underlying metabolic mechanisms. The Henske lab provides an ideal environment to reach this goal, with a very close relationship with experts from the field. I will continue to participate in three weekly scientific seminars, at which I will speak on a rotating basis. One of these is focused almost entirely on TSC and includes three other TSC-focused laboratories (David Kwiatkowski, Mustafa Sahin, and Carmen Priolo). Through my research in the Henske lab and with Dr. Henske s continued guidance, I wish to further develop my career as a basic and translational TSC scientist and become an independent investigator. Ultimately, the goal of this project is to develop new treatment strategies for TSC that will not require continuous, lifelong therapy. This could represent a significant advancement in the clinical care of individuals with TSC. Since MTX and the other agents that will be studied are already FDA-approved, this project has the potential to move quickly to clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710343
Entities
People
- Amine Belaid
Organizations
- United States Army