Abstract A2: Using plexiform neurofibroma preclinical therapeutics to help guide clinical trials
Authors: Wu Jianqiang , Jousma Edwin , Rizvi Tilat , Dunn Richard Scott , Jones David R. , Cripe Timothy P. , Kim Mi-Ok , Marcus Leigh , Dombi Eva , Baldwin Andrea , Long Lauren Meyerson , Andrea Gillespie , Whitcomb Patricia , Peron Staci Martin , Widemann Brigitte , Janhofer David , Ratner Nancy 
Published: May 2015

Abstract
Background: Neurofibromatosis type 1 (NF1) patients are predisposed to develop benign plexiform neurofibromas (PNs) that cause substantial morbidity. Surgery, the only standard treatment, is not feasible for most tumors. The NF1 gene product accelerates Ras-GTP hydrolysis to Ras-GDP and thus functions as a potent negative regulator of Ras. We developed a genetically engineered mouse model of neurofibroma, DhhCre;Nf1fl/fl, for use in preclinical testing; response is monitored by MRI imaging and volumetric analysis in conjunction with pharmacokinetic and pharmacodynamic readouts. The most effective neurofibroma therapy in this neurofibroma mouse model to date is drug candidates targeting inhibition of MEK1/2 (Jessen, W. et al., J. Clin. Invest., 2013).
Results: We have continued study of the allosteric MEK inhibitor PD-0325901 using the DhhCre;Nf1fl/fl model. To establish a minimum effective dose (MED) in this mouse model we administered doses of 0.5 – 10mg/kg/day for 2 months. Neurofibromas shrank at all dose levels, correlating with significant reductions in cell proliferation and tumor vasculature, despite significant differences in PD-0325901 blood levels. To test if early MEK inhibition prevents neurofibroma growth, we administered 1.5 mg/kg/day PD-0325901 before tumors formed in the mouse, for 3 months. Neurofibromas formed, but their size was reduced. There were no rebound effects off drug. Selumetinib (AZD6244; ARRY-142886), an orally bioavailable inhibitor of MEK1/2, is being tested in a Phase 1 trial in individuals with NF1 and inoperable PNs, with response monitored using MRI and volumetric analysis. Selumetinib is administered twice daily on a continuous dosing schedule (1 cycle=28 days); the maximum tolerated dose (MTD) is determined based on toxicities observed during the first 3 cycles. To date 12 subjects (median age 14 years, range, 5-18 years) have been enrolled. Six subjects each have been treated with 20 mg/m2/dose (50% of the dose recommended in adults with solid tumors) or 30 mg/m2/dose. The most frequent adverse events included acneiform rash, asymptomatic CPK elevation, and mild gastrointestinal toxicity. Dose limiting toxicities (DLT) in 2 of 6 patients at the 30 mg/m2 dose level were asymptomatic and reversible CPK elevation (n=1) and decrease in left ventricular ejection fraction (n=1), so this dose exceeded the MTD. Only 1 of 6 patients enrolled at the 20 mg/m2 dose level developed DLT (cellulitis); this dose has been identified as the MTD for this patient population. Partial responses (PN volume decrease ≥20%) have been observed at both dose levels in 5/9 subjects. Tumor shrinkage occurred slowly over time in progressive and non-progressive PNs, and progressive disease has not been observed to date. Enrollment on this study is ongoing, and a Phase 2 study is being planned.
Conclusions: A genetically engineered mouse model of neurofibromatosis is predictive of response to therapy in human NF1, supporting use of a drug testing platform that integrates mouse models and human trials. MEK inhibition downstream of Ras-GTP may be effective as a single agent, at low doses, to treat pediatric patients with neurofibroma and warrants further study. Supported by NIHP50-NS057531 and the Children's Tumor Foundation Neurofibromatosis Therapeutic Consortium to NR.
Citation Format: Jianqiang Wu, Edwin Jousma, Tilat Rizvi, Richard Scott Dunn, David R. Jones, Timothy P. Cripe, Mi-Ok Kim, Leigh Marcus, Eva Dombi, Andrea Baldwin, Lauren Meyerson Long, Gillespie Andrea, Patricia Whitcomb, Staci Martin Peron, Brigitte Widemann, David Janhofer, Nancy Ratner. Using plexiform neurofibroma preclinical therapeutics to help guide clinical trials. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A2.