Use of a genetically engineered murine model to identify novel experimental therapeutics for plexiform neurofibromas

Wade Clapp,

Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, IN.

Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression. Germline mutations in the NF1 tumor suppressorgene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in a genetically engineered murine model that is both genotypically and phenotypically similar to plexiform neurofibromas in NF1 patients, we have found that a multi- receptor tyrosine kinase inhibitor (imatinib mesylate) that targets c-kit, PDGF, and c-abl reduces plexiform neurofibromas.  In addition in a proof of concept patient and in a pilot phase 2 trial, a number of human tumors stabilized or were reduced as well. Ongoing studies in the laboratory supported by a UO1 mechanism are designed to evaluate whether other drugs that have a different spectrum of activity have comparable or greater efficacy as single agents or in combination with imatinib.     Of the 10 drugs screened to date 2 drugs passed both short term and long term treatment objectives that included, reducing the size of the tumors by 50% and reducing the absolute number of tumors by 25% or more.  Work is underway to move these drugs forward into phase 1-2 clinical trials.

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