Targeting TSC by mTORC1-Specific Bi-Steric Inhibitors
Abstract
Tuberous sclerosis complex (TSC) is a disease caused by mutations in either TSC1 or TSC2. TSC patients are commonly treated with inhibitors of the mammalian target of rapamycin (mTOR), everolimus or rapamycin. Although helpful, these drugs typically decrease tumor size only a little, and tumors regrow quickly when patients stop taking the drugs. In addition, these drugs have side effects, which include mouth sores, high cholesterol, irritation of the lungs (interstitial pneumonitis), delay in puberty (especially in girls), and suppression of immune system. Therefore, continuous and lifelong treatment is problematic. We have recently begun work with novel mTOR inhibitors, bi-sterics, which more effectively block mTORC1 activity than any rapalog medication that has been developed. In our hands, these bi-steric drugs appear more effective than rapamycin in several mouse model systems and trials in humans with these compounds are in progress. Our long-term goal is to validate the therapeutic effect of these novel bi-steric mTOR inhibitors in additional TSC/lymphangioleiomyomatosis (LAM) cells and mouse models, to examine in greater detail how they work, and explore the benefit of these novel mTOR inhibitors in rapamycin persistent cells. Our preliminary studies suggest that bi-steric drugs are better than rapalogs. In addition, these drugs are just entering clinical trials in human patients, so that there is potential for trials of these compounds in TSC patients in the near future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210547
Entities
People
- David J Kwiatkowski
Organizations
- United States Army