Office: RI 5900
D. Wade Clapp, MD
Richard L. Schreiner Professor and Chairman, Department of Pediatrics
Clinical Section: Neonatal-Perinatal Medicine
Professor Basic Science Joint Appointment: Microbiology and Immunology
- Fellowship: Hematopoiesis Core Laboratory, Ireland Cancer Center
- Neonatology Fellowship: Case Western Reserve University, Cleveland, OH
- Pediatrics Residency: Indiana University, Indianapolis, IN
- MD: Indiana University, Indianapolis, IN, 1982
Our laboratory focuses on the molecular pathogenesis of neurofibromatosis type 1 and neurofibromatosis type 2. Neurofibromatosis type 1 is the most common genetic disease with a predisposition to cancer and one of a series of developmental disorders called Rasopathies that have a range of malignant, neurodevelopmental and other non-malignant disease manifestations. A major effort in the laboratory is understanding the genetic, biochemical and cell-cell interactions that lead to the genesis and progression of plexiform neurofibromas that are often congenital in origin and become clinically apparent in babies and young children. To elucidate key pathological cell-cell and hyperactive Ras-mediated signaling pathways we utilize a genetically engineered murine model that closely recapitulates the steps in plexiform neurofibroma formation in humans that was originally developed by Dr. Luis Parada and students in his laboratory. Given the intractability of targeting Ras directly, our laboratory has to date focused on genetically disrupting components of the Ras pathway, both using mouse genetics and subsequently by pharmacologic inhibition. Molecular targets that have been identified in the lab as having a significant therapeutic effect are then moved forward into phase 1 and phase 2 clinical trials and an FDA RO1 sponsored clinical trial is anticipated to start in 2015. The drug discovery work has been supported with support from NINDS via a UO1 mechanism, in the context of a preclinical consortium of investigators supported by Neurofibromatosis Therapeutics Acceleration Program (NTAP) and the Children’s Tumor Foundation (CTF) and a SPORE application that will start this fall. Three drug targets tested in our preclinical model have now moved forward to the clinic.
Our efforts in neurofibromatosis type 2 are more recent. Building on the novel Nf2flox/flox mouse originally developed by Dr. Marco Giovannini, we have generated a murine model that accurately recapitulates the genesis of human vestibular and paraspinal schwannomas with 100% penetrance. Much like the efforts in NF1, we are utilizing the model in part to better understand the molecular pathogenesis of schwannoma formation. In addition, we are collaborating with other investigators in a multi-investigator initiative focused on identifying novel experimental therapeutics (Synodos) sponsored by the Children’s Tumor Foundation.