Toward Pharmacological Rescue of TSC Loss of Function
Abstract
BACKGROUND. This project aims to address the FY20 TSCRP Area of Emphasis: Eradicating tumors associated with TSC and TSC-associated lymphangioleiomyomatosis (LAM), including gaining a deeper mechanistic understanding of TSC signaling pathways. Currently, the only approved pharmacological intervention for TSC is via the direct mTOR inhibition by rapamycin or its synthetic analogs (rapalogs). Acute rapalog treatments initiate apoptosis within tumors of TSC mouse models, and chronic treatment blocks tumor formation and causes tumor regression. However, once the treatment is discontinued, the tumors regrow and the function of affected organs continues to decline. A would-be solution might involve chronic administration of the drug. However, prolonged exposure to rapalogs is associated with many adverse effects which might make it undesirable for widespread use in TSC patients. These include immunosuppression, insulin resistance and impaired glucose homeostasis. Consequently, there is an urgent unmet need to develop truly potent therapies with no or limited side effects for the treatment of TSC. HYPOTHESIS. We hypothesize that small-molecule chemical probes specifically targeting mTORC1docking on the lysosomal surface will lead to effective therapies against tuberous sclerosis complex. We propose a shift in target focus - from the mTOR kinase itself to the molecular event of mTORC1 docking on lysosomal membranes. SPECIFIC AIMS. The general aim of this proposal is to develop chemical probes that bind to and/or disrupt protein machinery responsible for anchoring mTORC1 on the lysosomal surface. Such disruption will limit the number of mTORC1 molecules that are activatable by upregulated Rheb in mutant TSC tissues.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2022
- Accession Number
- AD1168867
Entities
People
- Jonathan Weissman
Organizations
- Whitehead Institute