Target Identification and modeling of NF1-associated low-grade glioma

Low grade gliomas (LGG) develop in ~20% of children with NF1, occurring most commonly within the optic pathway (optic pathway glioma; OPG). While the majority of these tumors are indolent pilocytic astrocytomas (Pas) which do no necessitate medical intervention, 30-50% of the NF1-OPGs cause visual impairment, precocious puberty, or neurological symptoms. The identification of prognostic factors to identify those tumors that are likely to require intervention is crucial to minimizing the morbidity of these tumors as well as to limit treatment to only at-risk tumors. In addition, the time-honored therapies for symptomatic NF1-LGG entail the use of genotoxic drugs (e.g., carboplatin, vincristine, vinblastine) that can also damage dividing cells in germinal zones critical for normal brain development in children. As such, there is a pressing need to identify molecular risk factors and treatments targeted to the cellular and molecular properties unique to NF1-LGG. Progress in this area has been hampered by the paucity of human tumors available for analysis in any one institution, reflecting the relative infrequency of biopsy/surgical resection, and the difficulty in establishing patient-derived xenograft models from those rare specimens obtained for study. In striking contrast, there has been an explosion in our understanding of the genetic and epigenetic events associated with sporadic PA, where surgical specimens are frequently obtained. In these studies, the most common genomic changes identified involve genomic rearrangements in which the kinase domain of the BRAF gene is fused to numerous other proteins. Similar to NF1-PA, sporadic PA tumors bearing BRAF variants exhibit ERK/mTOR signaling pathway hyperactivation. Based on these studies, targeted therapies using MEK and mTOR inhibitors are now being evaluated in clinical trials.

In order to accelerate progress aimed at identifying the cell-intrinsic and cell-extrinsic molecular changes that dictate NF1-LFF biology and evaluate their functional significance relevant to the design of future NF1-LGG-specific targeted therapies, we have assembled a highly interactive and independently accomplished team of investigators with expertise in low-grade glioma mouse modeling (Gutmann, Weiss, Pfister), multi-scale genomic analyses (Pfister, Jones), tumor microenvironment influences (Phillips, Gutmann), signaling pathway growth control (Gutmann, Weiss, Resnick, Waanders), and the clinical management of children with NF1 and sporadic LGG (Fisher, Gutmann, Witt).