Targeting the Angiotensin Receptor in TSC
Abstract
Tuberous sclerosis (TS) is characterized by tumors in different parts of the body such as the brain, skin, and kidneys in addition to the development of lymphangioleiomyomatosis (LAM), a rare cystic lung disease, which can occur also in sporadic fashion. Importantly, both diseases share the same type of genetic error, which results in increased activity of a protein called mTOR that allows cells to have uncontrolled growth as seen in tumors. In preliminary data, we found that treating cells that are lacking TSC2 with a combination of rapamycin and losartan (a blood pressure pill) that blocks the angiotensin pathway leads to death of these cells. We also found that treating mice carrying tumors deficient in TSC2 leads to delayed tumor regrowth compared to rapamycin alone. We plan to understand how the combination of these two medications leads to cell death. We believe it is related to increased levels of a protein called klotho, which has been shown to be a tumor suppressor. We will also use this combination in animal models of TSC and LAM to show that once animals are treated with the combination, tumors do not re-grow once therapy is stopped. Finally, in serum from patients with LAM and TSC-LAM, we will measure klotho and related proteins levels to see if they are good indicators of disease when they are used alone or in combination with VEGF-D. At the conclusion of this project, we hope to establish that klotho is important in disease pathogenesis. More importantly, we hope to show that a combination of rapamycin and losartan can be effective in the treatment of LAM and other TSC-related diseases. The translation of our findings to patient care can occur quickly since both medications are Food and Drug Administration-approved.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910250
Entities
People
- Souheil El-chemaly
Organizations
- Brigham and Women's Hospital
- United States Army