Tuberous sclerosis complex (TSC) is a genetic disease in which tumors develop in multiple organs. TSC is caused by a mutation in the TSC1 or TSC2 gene, leading to activation of the mammalian target of rapamycin complex 1 (mTORC1). Treatment with mTORC1 inhibitors (rapamycin, everolimus) shrinks tumors in TSC, but the tumor cells are not killed. When treatment is discontinued, the tumors regrow. Hence, continuous therapy is needed. Treatments for TSC that kill the tumor cells are not currently clinically available, thus identification or development of such a treatment would have a major clinical impact. It is expected that after such a treatment, tumors would not reoccur, or growth would be very slow.

RNA transcription is the cellular process in which genes are “written” (transcribed) into RNA, which is then translated into protein. Proteins comprise the major component of cells, and direct cells in various ways including cell movement and cell growth.

Our colleagues in Boston identified THZ1 as a selective inhibitor of RNA transcription and found that it had cell killing effects for several cancer types both in cell culture systems (“in vitro”) and in preclinical mouse cancer models (“in vivo”). Transcription is an extremely important process in the cell, and recently there has been increased focus on the process of transcription as a potential therapeutic strategy. In particular, some cancer cells show “transcriptional addiction,” meaning that a gene is expressed and is absolutely required for the survival and development of that cancer, hence representing a prime therapeutic target.

I have already shown in two different cell types that THZ1 causes cell death in cells lacking TSC1 or TSC2. I also have important insight into how THZ1 causes cell death in such cells, but not normal cells. Furthermore, I have already shown in one preclinical mouse model of TSC that THZ1 is highly effective at inhibiting tumor growth, and this persisted for the full experimental duration, many weeks after treatment was stopped.

In this project, I will examine this correlation between genetic status and THZ1 sensitivity in more detail, using additional cell lines. I will also examine the molecular mechanism by which THZ1 causes cell death. Finally, I will assess the therapeutic potential of THZ1 alone and in conjunction with rapamycin in additional mouse models of TSC.

Ultimately, the goal of this project is to develop a new treatment strategy for TSC tumors that will not require continuous lifelong therapy. This could represent a significant advance in the clinical care of individuals with TSC. THZ1 derivatives (SY-1365) that are better tolerated in mice and humans are being actively pursued by Syros Pharmaceuticals, and early clinical trials of SY-1365 in humans are beginning. This suggests that these or related compounds will be available for TSC patients in the near future.