Defining the Cell Cycle Phase-Specific Regulation and Function of mTORC1 to Identify New Therapeutic Targets in TSC Tumors
Abstract
People with Tuberous Sclerosis Complex (TSC) are at risk of developing tumors in many organs, including the brain, heart, lungs, kidneys, and skin. The current standard-of-care drugs that are used to treat TSC tumors (rapamycin and its analogs) can halt or shrink tumors, but do not kill the tumor cells. Thus, tumors are not eliminated, and they can re-grow rapidly when the treatment is discontinued, underscoring the urgent need for new and improved therapies. This project will provide new understanding of the molecular events that occur in tumor cells in TSC and test a new strategy to selectively kill those cells, with the potential to eliminate tumors, thereby advancing the Fiscal Year 2022 Tuberous Sclerosis Complex Research Program Idea Development Award Focus Area of gaining a deeper mechanistic understanding of TSC signaling pathways and developing new strategies for eradicating TSC tumors. At the molecular level, tumor cells in people with TSC typically contain genetic mutations that inactivate a critical group of proteins called the TSC complex. The TSC complex normally blocks the activity of another group of proteins called mTOR complex 1 (mTORC1), so mutations in TSC patients cause uncontrolled mTORC1 activation. Uncontrolled mTORC1 activation drives tumor growth in TSC and is blocked by rapamycin to halt tumor growth. Much effort has been focused on understanding the regulation and function of the TSC complex and mTORC1 to develop new treatments for TSC tumors, but many critical questions remain. This project will study the TSC complex and mTORC1 in a way that has seldom been done in the field, but nevertheless is essential to understanding their regulation and function, as well as tumor growth, in TSC. All proliferating cells, including tumor cells in TSC, go through a cell cycle comprised of different phases in which cells accomplish different tasks so they can grow and divide into new cells. Most common experimental techniques combine thousands of cells from various phases of the cell cycle and therefore lose any information about what happens in specific cell cycle phases. For this reason, very little is known about how the TSC complex and mTORC1 differ from one cell cycle phase to another and whether they have functions that are uniquely essential only in specific phases. Discoveries of phase-specific functions could provide a wealth of new opportunities for targeting TSC tumors, so this represents a fundamental and highly significant gap in our understanding of the TSC complex, mTORC1, and Tuberous Sclerosis Complex. We hypothesize that the TSC complex and mTORC1 have differential functions throughout the cell cycle that could provide new therapeutic targets for treating TSC tumors. This hypothesis is strongly supported by our extensive preliminary data, in which we studied the TSC complex and mTORC1 throughout the cell cycle and discovered two new molecular events that only occur in specific cell cycle phases. One of these events is an important modification of the TSC complex that only occurs when cells are dividing, strongly suggesting that it plays a critical, but currently unknown, role during that time. The other key discovery is a new role for mTORC1 in controlling cellular metabolism to support cell growth and proliferation, which provides a compelling new target for eliminating TSC tumors. In this project, we will rigorously and systematically determine how these events are controlled and what their functions are in order to determine whether they could be exploited to develop new therapies for TSC. As proof of principle, our previous studies demonstrated that targeting metabolic pathways controlled by mTORC1 can induce potent and selective TSC tumor cell death, indicating that this strategy could have significant advantage over the current therapies. However, we have only scratched the surface with regards to identifying and exploiting targetable metabolic vulnerabilities. Thus, we w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310288
Entities
People
- Alexander Valvezan
Organizations
- Rutgers University
- United States Army