We recently identified the MEK inhibitor selumetinib as the first active agent against NF1 PN. In a phase I clinical trial for children and young adults with inoperable PN we reported tumor shrinkage in 71% of patients. Subsequently we developed a phase II clinical trial in collaboration with 3 other sites. This trial incorporated standardized patient reported and functional outcome measures in addition to assessment of response by volumetric MRI analysis. We recently reported that this larger phase II trial confirmed the previously reported response rate of 71%. In addition, we observed clinically meaningful improvement in pain and function and lesser disfigurement. We are collaborating with the participating sites, NCI CTEP, and the pharmaceutical company in a planned submission of this data to the FDA. In addition, we have opened a phase Ii clinical trial of selumetinib for adults with NF1 and inoperable PN, which is actively enrolling patients. We are continuing enrollment on our NF1 natural history study to assess changes in tumor burden over time and to identify biomarkers of malignant transformation. We are also studying the immune infiltrate in tumors and immune cells in peripheral blood of patients with NF1 in collaboration with Jane Trepel's lab in the CCR in the hopes to develop rational immunotherapy approaches for NF1 related tumors. We have made substantial progress in the understanding of peripheral nerve sheath tumors called atypical neurofibromas (ANF). We and our collaborators comprehensively analyzed the clinical presentation and management of these tumors. In contrast to PN, ANF have heterozygous loss of CDKN2A/B. This loss is also found in MPNST, but not in benign PN. We therefore believe that ANF are precursor lesions to MPNST and require close clinical monitoring and resection, if it can be performed with minimal morbidity. Some patients with NF1 have multiple ANF or have ANF in locations, which are not amenable to surgery easily. We are currently developing a clinical trial of a CDK4/6 inhibitor specifically for patients with NF1 and unrespectable ANF. This will be to our knowledge the first interventional trial targeting ANF. In collaboration with several extramural investigators we are working on the development of new trials including combination therapies for NF1 related PN and MPNST. For example, a clinical trial for MPNST combining a checkpoint inhibitor, a MEK inhibitor, and a bromodomain inhibitor is in development based on data from the Cichowski lab.
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