MPNSTs are the most commonly lethal feature associated with NF1. These tumors are highly aggressive and frequently metastasize. Consequently, greater than 50% of NF1 patients with MPNSTs present with inoperable disease. Despite radiation and in some cases chemotherapy, inoperable tumors rapidly progress and are typically lethal. As such, identifying an effective treatment for these tumors is critical.

The emergence of new, targeted "smart" therapies has made a dramatic impact on the treatment and survival of patients with other cancers, such as leukemia and lung cancer. We have been using human tumor samples and sophisticated mouse models to identify similar therapies for MPNSTs. We have found that the key lies in combining two different drugs that attack the cancer cells at the same time. In this application, our first goal is to test several different rationally designed drug combinations in our mouse model to identify the best combination among many possibilities. In a sense, we will be performing mini clinical trials in mice. Second, we will study these mice to understand how effective combinations are working. Third, we have set up collaborations with physicians involved with the NF1 Clinical Consortium and pharmaceutical companies to directly bring the most effective therapy(ies) to clinical trials. Notably, through these efforts we have already successfully brought two trials to the clinic, one in MPNSTs and one in lung cancer, and a second trial in MPNSTs is in development.

Our sole goal is to develop effective therapies for patients with MPNSTs. Based on our promising preliminary results, our dedication to this effort, and the strong collaborative relationships that we have established, these studies have the potential to change the standard of care for patients with MPNSTs in the very near future. The first clinical trial inspired by this work could begin within the first year of funding, with secondary trials to follow. In addition, while many individuals with MPNSTs also have neurofibromas, future clinical trials should provide a preliminary indication of whether these therapies might be effective on these tumors as well. Regardless, we already closely collaborate and share insight with our colleagues that study neurofibromas so that our insights will benefit the greatest number of people.