Preclinical-clinical trials collaboration to effectively advance new combination therapies for atypical neurofibroma in neurofibromatosis type 1

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PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome characterized by the development of a spectrum of benign and malignant tumors of the peripheral nervous system. Individuals with benign plexiform neurofibromas (PNF) are at increased risk of developing malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue sarcoma that rapidly progresses and is uniformly fatal in patients who present with unresectable disease. The majority of NF1 MPNST arise from pre-existing neurofibromas, suggesting that these precursor lesions hold important clues to the developmental origins of MPNST and for identifying novel therapeutic strategies for MPNST treatment and prevention. Work by our team of intramural and extramural investigators has demonstrated that malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF), characterized by distinct histopathological and molecular features including copy number loss of the CDKN2A/B tumor suppressor locus. Natural history data shows that these pre-malignant lesions are direct precursors of MPNST. While clinical trials lead by our group have spurred transformative advances for the treatment of NF1-associated PNF, including FDA and EMA approval of selumetininb (MEK inhibitor) for the treatment of pediatric PNF, we have discovered that MEK inhibition does not induce treatment responses in most ANF and does not appear to prevent MPNST. Surgical resection of ANF has become a strategy to prevent MPNST. However, surgery may be associated with significant morbidity or infeasible due to ANF location or presence of multiple ANF. To address the challenges of treating and preventing malignant transformation of ANF precursor lesions in this vulnerable patient population, we will leverage a robust infrastructure spanning the preclinical-to-clinical continuum to rapidly test and translate novel therapeutic strategies to the clinic for the treatment of ANF and to identify response biomarkers. Our work will center on CDK4/6 inhibition to strategically oppose the dysregulated signaling induced by CDKN2A/B loss. The overarching goals of this project are to (1) develop single agent and/or combination therapies for ANF informed by preclinical murine models that spontaneously develop ANF and MPNST, allowing interrogation of therapeutic interventions at each stage of tumor progression, (2) establish a pipeline to accelerate the translation of first-in- kind therapies to the clinic to effectively treat ANF and prevent malignant transformation, and (3) identify robust molecular biomarkers associated with treatment response. Harnessing the specialized expertise of translational and clinical investigators at the NCI, and extramural experts in NF1 biology and therapeutic development, this collaborative effort will employ state-of-the-art approaches in preclinical modeling, window of opportunity trials, single cell analytics, and non-invasive liquid biopsy coupled with integrative multi-omic profiling to understand ANF to MPNST evolution and drive therapeutic innovation for increasingly aggressive orphan cancers where no current treatment options exist.