Maintenance of Genome Stability in TSC2-Deficient Tumors
Abstract
Tuberous sclerosis complex (TSC) is a genetic disease. Mutations in either TSC1 or TSC2 are found in 85% of TSC patients, and the majority of patients have TSC2 mutation. Patients with TSC usually have benign tumors during childhood in many parts of bodies, including brain, kidney, and lung. Despite excessive growth signaling provided by mTORC1 hyperactivation, TSC-deficient tumors can retain their benign molecular features and usually do not undergo malignant transformation and thus develop malignant tumors such as cancers in TSC. It remains to be an important gap in knowledge to understand how TSC-deficient tumors maintain genomic stability and thus exhibit an intrinsic resistance to mutator phenotype, which underlies malignant transformation. Although TSC-deficient tumors are benign, they may cause severe clinical symptoms. More than 80% of TSC patients have central nervous system complications, such as seizures, mental retardation, and autism. Renal tumors (bilateral renal angiomyolipoma, hamartoma, or cysts) cause the most lethal complications for TSC patients including end-stage renal failure, massive bleeding, or infection. Some TSC patients, especially women, develop chronic obstructive pulmonary disease due to pulmonary lymphangiomyomatosis. Inhibition of mTOR activity by rapalogs is one of a few strategies to control tumor growth in TSC patients. However, not all patients respond to rapalogs or can tolerate adverse effects of rapologs, such as immune suppression. Therefore, there is an urgent clinic need to identify alternative effective therapies that can selectively target TSC-deficient tumors. My laboratory is focused on studying the network of DNA repair and DNA damage response in genome maintenance. In our preliminary studies, we have discovered a novel and unexpected role of the mTORC1 complex in regulating mutagenic repair and cell cycle recovery in the presence of DNA double-strand breaks. In this application, we propose to study how mTORC1 hyperactivation in TSC-deficient tumors represses the low fidelity DNA repair pathway and thus promotes the high fidelity DNA repair pathway, which may prevent accumulation of extensive mutations in TSC-deficient tumors. We believe our results will open new avenues for our understanding how mTORC1 signaling functions as a convergent point to link nutrient availability sensing and DNA repair fidelity. The new finding from our project will not only fill an important gap in knowledge in TSC studies, but also deepen our understanding of mutator phenotype and genomic instability driven by low nutrient availability in human cancers. Furthermore, TSC-deficient tumors show an accelerated cell cycle transition in the presence of DNA damage. They exhibit a fast recovery from DNA damage-induced cell cycle arrest. In this application, we will explore whether this molecular consequences caused by TSC deficiency creates a therapeutic vulnerability to target TSC-deficient tumors by using inhibitors of DNA damage checkpoint kinases. This therapeutic approach is a novel and fundamentally different strategy to combat TSC. We aim to target molecular consequences caused by mTORC1 hyperactivation, namely accelerated cell cycle recovery after DNA damage, rather than targeting mTORC1-realted growth signaling, such as rapalogs. This therapy strategy is targeting specific molecular defects that only exist in TSC-deficient tumor cells. We expect this approach will selectively inhibit TSC-deficient tumor cells with minimal harm to normal cells. WEE1 inhibitor AZD1775, which we propose to study as a targeted therapy for TSC-deficient tumor in this application, has been shown to be safe in Phase I trials and is currently being tested in Phase II trials. As a single agent, AZD1775 is well tolerated, making it an ideal agent for combination studies. Thus, if our study is successful, our results will have significant positive impact for TSC patients and can be readily tran
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910459
Entities
People
- Guang Peng
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army