Enhancing MAPK-targeted Therapy in PDX Models of BRAF-Mutant Pediatric Brain Tumors

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Pediatric glioma is characterized by activation of the MAPK pathway, either through a tandem duplication of the BRAFA locus, or through point mutations (most frequently the V600E mutation). Approximately 1400 new cases of BRAF-activated childhood brain tumors are diagnosed annually in the US. Recent phase I/II trials have confirmed the efficacy of MEK inhibitors ((MEKi) for teatment of these cancers. However, for tumors driven by the BRAF(V600E) mutant patients may progress on selumetinib treatment (i.e. become resistant), or rapidly progress if drug dose is reduced or treatment stopped (at 2 years as in the recent phase II trial). Thus, while MEKi is effective in causing tumor regression, it is not curative. Clinical results suggest that selumetinib is equally as effective as conventional chemo-radiation therapy, but without toxicities associated with intensive chemo- radiation treatment. Hence, MEK inhibitors usher in a new era in treatment for these patients. Our studies were some of the only PDX preclinical data that lead to testing of selumetinib (MEK inhibitor) in the Pediatric Brain Tumor Consortium trial (PBTC029), with efficacy confirmed in the subsequent phase II trial (NCT01089101). Here we propose preclinical studies that could lead to the next generation of clinical trials building on the results from current MEKi trials. The studies proposed in this application will use a unique panel of BRAF(V600E) pediatric brain tumor PDX models to focus on two critical issues: 1) to develop MAPK inhibitor combinations that selectively enhance tumor cell kill in combination with radiation therapy (RT), and 2) to develop therapeutic approaches to prevent development of drug resistance. The central hypothesis is that sensitivity to MAPKi is a consequence of dual MAPK/TORC1 inhibition, and low-dose intermittent rapamycin can prevent emergence of resistance to MEKi, and also to radiation therapy. These studies will also explore mechanisms of resistance to MAPK inhibitor combinations and radiation treatment (RT), alone or in combination, and characterize the mechanism/s by which rapamycin prevents emergence of resistance. Our overall goal is to identify optimal MAPK/TORC1 inhibitor drug combinations that retard or prevent emergence of drug or RT resistance, determine the mechanism/s by which rapamycin retards/prevents emergence of MAPKi and RT resistance, and determine whether such combinations can maintain tumor control at lower doses of RT. Potentially, the proposed studies will identify novel regimens that will be more efficacious than selumetinib and ultimately result in the ability to reduce the RT dose in patients, thus improving long-term outcomes and quality of life.