Jonathan Chernoff, MD, PhD (Fox Chase Cancer Center) and Wade Clapp, MD (Indiana University) were recently recommended for funding by the Department of Defense office of the Congressionally Directed Medical Research Program (CDMRP), for the Fiscal Year 2013 Neurofibromatosis Research Program (NFRP) Investigator-Initiated Research Award. The joint application is slated to receive $575K for “Testing the role of p21 activated kinases (PAK) in schwannoma formation using a novel genetically engineered murine model that closely phenocopies human NF2 disease”. This is not only a great follow-on project for the CTF-funded research of the two principal investigators, discovery of PAK inhibitors as useful molecules (Chernoff), and the creation of new genetically engineered murine model for NF2 (Clapp), but also a great return on investiment (ROI) of CTF funded NF2 research within the NF Preclinical Consortium. Please see below for more detail.
“This proposal focuses on the role of p21-activated kinases (PAKs) in NF2 tumorigenic signaling in vivo, with the aim of establishing these kinases as plausible therapeutic targets for the treatment of NF2 in the immediate future.
“The proposed studies represent the culmination of a series of experiments dating back nearly a decade that tie Merlin to PAK function. The Clapp and Chernoff labs have here joined forces to assemble the most advanced mouse models and pharmacological tools to establish the value of PAKs as therapeutic targets in NF2. We are poised to carry out definitive preclinical tests, thus setting the stage for human trials of science-based targeted agents in NF2.
“The NF2 field has been held back by a lack of satisfactory animal models and a lack of tractable drug targets. In the application we address both issues. The new genetically engineered mouse model that we propose to use represents the most useful preclinical model of NF2 created to date, including the development of vestibular schwannomas that result in hearing loss. Similarly, PAKs represent the best understood and authenticated targets in Merlin signaling, and we are now at the stage where the pharmaceutical industry has provided advanced-stage anti-PAK compounds for preclinical testing.
“Our hypothesis is that inactivation of the NF2 gene disrupts a tumorigenic signaling pathway emanating from the small GTPase Rac and its effector, PAK. We propose that stimulation of the Rac/PAK signaling axis in cells lacking Merlin leads to changes in transcriptional activity and cytoskeletal dynamics, ultimately resulting in enhanced cell proliferation and motility, which are hallmarks of tumorigenesis. If this hypothesis is correct, then inhibition of PAK signaling should disable the growth advantages of cells lacking Merlin. We intend to test this theory directly using both genetic and pharmacologic approaches, employing the most advanced NF2 models developed to date as well as “next-generation” PAK inhibitors. We expect that the results of this study can be used to inform a clinical trail within the lifetime of this grant.”
