Novel Inhibitors of MPNST
Abstract
Rationale and Objective: Mutations in the NF1 gene cause neurofibromatosis 1 disease. These mutations suppress the ability of the NF1 protein to control the activity of the notorious RAS oncoproteins. Thus, RAS oncoproteins become more active than they should be naturally. This over-activation is a key component of the development of the highly dangerous Malignant Peripheral Nerve Sheath Tumors (MPNST) that can arise in NF1 patients. The most logical approach to treating the symptoms of NF1 disease would therefore be to try and inhibit the over-activity of the RAS proteins. Unfortunately, to date, no clinically effective inhibitors targeted at RAS have been developed. We have discovered two different small molecules that can act to inhibit the function of RAS oncoproteins. One binds directly to the RaAS protein to block its action. The second is designed to act indirectly on RAS by preventing RAS from interacting with some of its critical binding partner proteins. Both of these molecules effectively suppress the ability of MPNST tumor cells to form tumor-like structures in tissue culture systems. Moreover, they have low toxicity and inhibit the ability of Ras- driven tumor cells to form tumors in animals. Our objectives are to test the compounds for the ability to act against human MPNST cell systems in vivo, both cell lines and the newly developed and highly physiological pdx systems from NTAP. Secondly, we wish to test them against a validated transgenic (immunocompetent) mouse model of MPNST with the assistance of collaborator Parada. Ultimate Applicability: Ultimately, we hope to develop our inhibitors into orally available drugs that can suppress MPNST growth and metastasis. What types of patients will it help and how will it help them? If successful, the proposal would help patients suffering from MPNST, a highly dangerous form of cancer, by serving a low-toxicity, highly effective targeted therapy. In the future, they might also help patients suffering from cognitive/learning difficulties due to the NF1 mutation by suppressing the over-activation of Ras pathways. What are the potential clinical applications, benefits, and risks? Clinical applications would involve taking the compounds or their enhanced derivatives (which we are currently working on) in a tablet form, possibly in combination with other targeted therapies to treat MPNST. A case could be made that the inhibitors might actually serve as preventative agents and could be taken to reduce the chance of MPNST occurring in the first place. The compounds also have the future potential to treat learning disabilities/cognitive dysfunction in NF1 patients. This approach would also involve long-term use of the drugs. At present, we have no truly long-term toxicity information, so there is a risk of toxicity or off-target effects. Part of this proposal involves a more thorough analysis of potential toxicity. However, the compounds are clearly non-toxic in the short term, as the animals do not seem to exhibit any negative effects (as measured by liver or kidney dysfunction) of exposure to the compounds over a course of several weeks. What is the projected time it may take to achieve a patient-related outcome? Our institution has a pipeline of compounds, directed at a range of different targets, originally identified by directed in silico screening for anti-cancer potential. The most advanced has now entered clinical trials after extensive Medicinal Chemistry optimization and animal safety studies. The overall process took approximately 10 years. We have already produced and screened over 60 derivatives and have identified compounds with significantly enhanced activity over the parentals (new drugs F3-158 and C4-180). Thus, we are already ~ halfway through the process. If the project were successful, an estimate of 5 years to patient testing would not be unreasonable, provided we can obtain financial support for pre-I
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910417
Entities
People
- Geoffrey Clark
Organizations
- United States Army
- University of Louisville