Defining Cellular Stresses Sensed Through the TSC Complex to Identify Vulnerabilities in TSC Tumors

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 can regrow rapidly when treatment is discontinued, underscoring the need for new and improved therapies. This project will advance our 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.

At the molecular level, tumor cells in people with TSC typically contain mutations that inactivate a critical group of proteins called the 'TSC complex.' The TSC complex ensures that cells only grow under appropriate conditions and thus its inactivation contributes to uncontrolled tumor cell growth. However, the TSC complex also normally detects various stresses that the cell encounters, and its inactivation can thus render cells unable to respond appropriately. This project will advance our understanding of this molecular 'double-edged sword' and how it can be leveraged to eliminate tumors in people with TSC. By gaining a better understanding of which stresses are sensed by the TSC complex, we can develop therapies that exacerbate those stresses and specifically kill TSC tumor cells as a result of their inability to respond.

This project will define a role for the TSC complex in sensing a common cellular stress that it is not currently known to respond to (DNA replication stress, i.e., stress that occurs when a cell cannot replicate its DNA to proliferate). This project will also test a new strategy to strongly induce DNA replication stress in TSC tumor cells, without affecting normal cells, using well-tolerated drugs that are already being used in human patients for other purposes. My preliminary data demonstrate that this strategy can potently and selectively kill cells that lack a functional TSC complex, and this project will confirm and extend these findings through rigorous testing in multiple TSC tumor models. These studies have the potential to eliminate TSC tumors and provide the preclinical data necessary to advance these treatments to clinical trials to benefit TSC patients. As the drugs that will be used here are already being used in humans, they could potentially be rapidly repurposed for use in TSC patients. Furthermore, by advancing our knowledge of the molecular function of the TSC complex, these studies will open up new areas of research that build on the concepts uncovered here to develop additional strategies for treating TSC-associated tumors.