Investigating Novel Targetable Vulnerabilities of LAM Disease
Abstract
We propose to undergo preclinical testing of a candidate drug that has recently entered clinical trials for lymphoma patients. We will test this drug in cells and mouse models of tuberous sclerosis complex (TSC)-associated tumors, including a model of pulmonary lymphangioleiomyomatosis (LAM). We also propose to investigate key aspects of TSC cell biology. This project is, therefore, responsive to the TSCRP area of emphasis Eradicating tumors associated with TSC and TSC-associated lymphangioleiomyomatosis (LAM), including gaining a deeper mechanistic understanding of TSC signaling pathways. Aberrant activation of mTORC1 is a hallmark of TSC. We have recently discovered that a drug that inhibits a cellular protein named N-myristoyltransferase (NMT) also decreases mTORC1 signaling in cancer cells. Following upon this observation, we reasoned that this NMT inhibitory drug (NMTi) could be efficacious against TSC-associated tumors. Our preliminary data using TSC2 mutant cells support this hypothesis. A limitation of current mTOR inhibitors used in the clinic to treat TSC and LAM is that they need to be taken for the rest of the patient’s life to prevent tumors from growing back. However, based on our results in TSC mutant cells, NMTi is different from mTOR inhibitors in that it has the potential to kill TSC mutant tumor cells and eventually be curative even after the treatment finalizes. Based on this exciting possibility, we want to investigate the effect of NMTi in TSC cells and tumors generated in animals. Indeed, we and others have used NMTi to successfully limit malignant carcinoma growth in animals. Furthermore, after injection of NMTi into animals, we did not observed any sign of toxicity. Similar toxicological results have been reported for mice, rats, and dogs before phase 1 trial approval, indicating the feasibility and therapeutic potential of the proposed study. In addition to perform these preclinical studies, we will use this drug as a tool to dissect the biology of TSC mutant cells with the goals of: (a) Understanding the specific mechanisms by which the NMTi drug works and selectively kills TSC mutant tumor cells. (b) Identifying additional specific vulnerabilities of TSC mutant tumors cells that can be exploited to design better treatments for TSC patients. Our study will move the field of TSC forward by improving our understanding of the pathobiology of TSC cells. Furthermore, we are excited about the possibility to find a curative drug for TSC-associated tumors and LAM that is efficacious when taken for a limited period of time. Our study is timely and significant, and, if successful, it will provide a rationale for testing this new drug in clinical trials designed for TSC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211029
Entities
People
- Begona Diaz
Organizations
- Harbor–UCLA Medical Center
- United States Army