Abstract IA24: Identification of therapies for plexiform neurofibromas, a precursor of malignant peripheral nerve sheath tumors

Abstract

Abstract Plexiform neurofibromas (PNs) are complex nerve and soft tissue tumors that affect 25-50% of individuals with neurofibromatosis type 1 (NF1), the most common genetic disease in man with a predisposition to cancer. PNs cause lifelong morbidity ranging from deformity to paralysis and mortality due to organ compression, and progress to MPNST in ~8-13% of patients. The generation of genetically engineered mouse models that closely recapitulate the development of human plexiform neurofibromas has allowed our laboratory and others to pursue genetic and pharmacologic studies to identify novel therapies. Genetic and adoptive transfer studies conducted by our lab in collaboration with Dr. Luis Parada identified a key role for c-kit/kit-ligand in tumor initiation and progression. These data led to a clinical trial administering imatinib mesylate to target aberrant stem cell factor (SCF)/c-kit signaling in the tumor microenvironment, which induced the only objective clinical responses ever obtained in a therapeutic clinical trial in pNF. Based on the observation that young children with head, neck, and airway tumors were most likely to have partial tumor regression, a registration trial in this patient population is currently being pursued. Further, additional phase 2 trials using other receptor tyrosine kinases that include c-kit are under way as well. More recently, studies in GEM models informed clinical trials of MEK inhibitors led by Dr. Brigitte Widemann (Pediatric Branch of NCI) to directly inhibit aberrant Ras signaling in PN cells. Studies are ongoing to extend these promising initial clinical findings to investigate the developmental, molecular, and pharmacokinetic effects of c-kit and MEK inhibition alone and in combination in preclinical models. Specifically, studies to explore adaptive responses to MEK inhibition monotherapy in mice and patients treated with selumetinib via integrated exome, RNAseq, and kinome studies in pre- and post-treatment tumor tissue are under way. Citation Format: D. Wade Clapp. Identification of therapies for plexiform neurofibromas, a precursor of malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA24.