Developing a translational pipeline for NF1-mutant malignancies

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 DESCRIPTION (provided by applicant): Neurofibromatosis type 1 (NF1) is a prevalent familial cancer syndrome affecting 1 in 3500 individuals worldwide. The most commonly lethal feature associated with NF1 is malignant peripheral nerve sheath tumors (MPNST). These soft tissue sarcomas are highly aggressive and frequently metastasize. Despite radiation and chemotherapy, inoperable tumors rapidly progress and are universally lethal. As such, identifying effective treatments for MPNST is critical. The primary goal of this application is to establish a robust preclinical/clinical pipeline (bench-to-bedside and back) to rapidly develop and test new (combination) therapies for this deadly malignancy. This effort will harness the specialized expertise of clinical investigators at the NCI and Children's National Medical Center, extramural experts in NF1 biology and therapeutic development, and will leverage the unique resources of the NIH Clinical Center. Specifically, new discoveries of mechanisms that drive NF1-related tumorigenesis together with recent insights into the immunoreactivity of MPNST will be used to develop rational combination therapies and will be tested in a robust preclinical MPNST mouse model (Karen Cichowski, BWH, extramural preclinical center). These insights will then be used to perform clinical trials in MPNST patients with an emphasis on evaluating more than one combination therapy within the same trial. This will allow for more timely identification of active agents, and allow patients with this highly refractory disease to have mor treatment options available to them (Brigitte Widemann, NCI, intramural clinical center). Furthermore, the preclinical to clinical translation will be complemented by comprehensive genomic and immunological analyses of tumor samples obtained prior to treatment and on treatment with novel agents in order to identify mechanisms of response and resistance and to identify additional potential targets for therapy in individual patients. As such, insight and samples from the clinic will serve as the foundation to develop new or improve existing therapies, thus highlighting the iterative and collaborative nature of this pipeline. Taken togethe, we have assembled a multi-disciplinary team of basic and clinical scientists from different fields to develop and translate promising therapies for individuals with MPNST. This effort includes experts in NF1 biology and therapeutic development, cancer immunobiologists, a diverse set of clinicians with expertise in MPNST and immunotherapy, and genomicists. Importantly, a subset of these investigators already have a track record of working together to develop new trials for MPNST patients. This grant will allow more effective and rapid translation of promising new therapies for MPNST, and will expand the type of (combination) therapies that are developed, by bringing in additional expertise and leveraging the unique resources of the Clinical Center. Ultimately, these studies have the potential to change the standard of care for the currently treatment refractory tumors associated with the common familial cancer syndrome NF1.