SIRT5, A Novel Therapeutic Target for NF1-Associated MPNST
Abstract
Rationale: This proposal focuses on developing new treatments for a devastating cancer associated with neurofibromatosis type 1 (NF1). NF1 is a common genetic condition that occurs in roughly 1 of every 3,500 people. NF1 is caused by DNA mutations in a gene called Neurofibromin 1, which in its normal state reduces certain types of signaling within cells. NF1 is a very complicated disease that involves many organ systems: the skin, the eye, internal organs, and especially the nervous system. The most feared complication of NF1 is an aggressive cancer called malignant peripheral nerve sheath tumor (MPNST). MPNST is resistant to standard cancer therapies, such as radiation therapy and chemotherapy. Surgical excision remains the only effective MPNST treatment. The 5-year survival rate of NF1 patients with MPNST remains a dismal 16%. Development of new therapies for MPNST is a pressing unmet need in NF1 clinical care. Our laboratory has generated exciting new findings in MPNST cells that may pave the way for development of new MPNST treatments. We study a family of proteins called the sirtuins, which regulate many targets and proteins within cells. Our new work has revealed that MPNST cells require one of the sirtuins, called SIRT5, to remain alive and grow. We found that, in all human MPNST cell lines tested, loss of SIRT5 resulted in rapid cell death. We and other groups have removed the SIRT5 gene from cells other than MPNSTs, and even from whole mice. Most cell types are able to survive and grow without SIRT5. Mice that lack SIRT5 are alive and healthy. Based on these findings, we believe that SIRT5 may represent an attractive therapeutic target for MPNST. Together with Dr. Nouri Neamati, a medicinal chemist at the University of Michigan, we have developed first-in-class SIRT5 inhibitors as new treatments for MPNST. For some of these, we have determined exactly how they interact with SIRT5. This will enable to us to modify these drugs to improve their pharmaceutical properties. Objectives: We will determine why SIRT5 is required for MPNST survival. We will develop better drugs that more efficiently inhibit SIRT5 function. We will test the ability of these drugs to kill MPNST cells in cultured cells, as well as those growing as tumors in mouse models. Impact: Our work could be applicable to any NF1 patient who develops MPNST. For individuals with NF1, the lifetime risk of developing MPNST is fairly high, 8 to 13%. Unfortunately, due to the lack of effective treatment approaches, most of these individuals will die within 5 years of MPNST diagnosis. Potential Clinical Applications, Benefits, and Risks: SIRT5 inhibitor drugs may be new, valuable additions to surgery in treating MPNST in patients with NF1. We predict that SIRT5 inhibitor drugs would kill MPNST cells, with little effect on normal cells and tissues. Studies of mice without the SIRT5 gene suggest that these drugs would be well-tolerated overall, since these mice are quite healthy. One group has shown that these mice develop mild defects in heart function as they age. However, SIRT5 inhibitors would be given over a fairly short time. It is unlikely that such treatment would cause such heart problems, which occur over a very long period in the mouse model. Projected Time Required to Achieve a Patient-Related Outcome: At the end of the 3-year period of Department of Defense support, we will have highly potent and selective SIRT5 inhibitors. In follow-up work, these drugs will be tested in additional mouse MPNST models to assess their safety and efficacy. Given the potential of safely inhibiting SIRT5, we foresee that such drugs could enter Phase I clinical trials within a reasonably short time. Great progress has been made in treating many of the complications of NF1. However, MPNST remains a devastating, frequently lethal manifestation of this disease. If successful, our studies will pave the way toward a new appr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810567
Entities
People
- David B. Lombard
Organizations
- United States Army
- University of Michigan