Exploring a Novel Signaling Node for Therapeutic Efficacy in MPNST
Abstract
The proposal presented here is in response to the FY18 Neurofibromatosis Research Program Exploration – Hypothesis Development Award. The Area of Emphasis that we will focus on is target identification, drug discovery, targeted and immunotherapies. We will focus on malignant peripheral nerve sheath tumors (MPNST) arising from patients with NF1 (neurofibromatosis type 1). These patients are at a much greater risk of developing MPNST than the general population (10% vs. 0.01%, respectively). This proposal is investigating a novel target that has been shown to drive aggressive and invasive cancers and is overly activated in several human cancers, including MPNSTs. Although many attempts have been made to discover new chemotherapeutic agents, MPNSTs respond poorly to existing chemotherapeutic agents, and new therapies are desperately needed. Therefore, our long-term goal is to develop a therapy that improves patient outcome by blocking a redox signaling protein called Ref-1 (redox factor-1). Redox signaling involves maintenance of transcription factors in a state by which they can turn on genes necessary for processes such as cell survival, expansion, and migration. The redox function of Ref-1 in the tumor cells is the focus of this grant due to its role in maintaining these transcription factors to promote resistance and growth of MPNSTs. The objective of this work is to determine the outcome of inhibiting the function of Ref-1 in MPNST tumor cells. The central hypothesis of the proposed work is that Ref-1 redox activity is critical for cell survival, and that our potent inhibitors will be an effective treatment in mouse models of human MPNST and eventually in humans. We have compelling data to demonstrate that Ref-1 is highly expressed in human MPNST, and inhibition of Ref-1 redox activity dramatically impedes the growth of human MPNST cancer cell lines in mice. Previous preclinical studies led to a phase I clinical trial (NCT03375086) of the Ref-1 targeting drug APX3330 in the treatment of solid tumors. We have a clinically tested, first-in-class inhibitor (APX3330) that is the first ever to reach the clinic targeting Ref-1 in cancer, making the translation of this work highly plausible for pediatric patients with MPNST in the future. This proposal addresses a fundamental gap in knowledge, as currently there is not an effective treatment for this disease. Furthermore, the team of investigators on this project possess critical expertise to ensure the findings are taken to translational fruition. Dr. Clapp is one of the principal investigators on the first Pediatric SPORE ever funded by the National Cancer Institute, entitled “The Developmental Hyperactive Ras Tumor (DHART) SPORE,” (MPIs: Wade Clapp (IUSM) and Kevin Shannon (UCSF)). One of the major areas of impact in this project is Dr. Clapp’s contribution of NF1 Genetically Engineered Models and human NF1 cancer models. Our team’s involvement in the DHART SPORE provides additional collective expertise and utilization of state-of-the art, novel technologies and models. Sharing of model organisms by SPORE investigators is a clear expectation, and all of the investigators participating in the SPORE are fully committed to sharing novel models and methodologies across institutions. The new collaborations and knowledge gained from this proposal may provide a therapeutic option in MPNSTs where few therapeutic options exist. If we are successful, we will have defined a critical therapeutic target for MPNST, and logically, clinical trials would follow targeting this pathway in patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910217
Entities
People
- Melissa Fishel
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army