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In 2006 the Children’s Tumor Foundation established the Drug Discovery Initiative Awards program to identify future candidates for clinical trials drugs by testing them either in cell or animal models of NF.  NF is well set up to do preclinical drug screening, since researchers have, over the past 10 years, developed a series of genetically-engineered mice that develop various features of NF1 and NF2 – various NF-associated tumors, bone dysplasia, even learning disabilities – and these are a terrific resource for testing drugs. DDI Awards are fairly modest - currently $15,000 for a cell-based study and $30,000 for an animal based study (largely mouse, but DDI studies in Drosophila (fruit fly) have also been funded) – and are intended to support initial proof of concept as to whether a drug has any potential at all as a candidate NF drug therapy. 

Three years on, we have funded 26 DDI Awards at a cost of $615,500 to test candidate NF1 and NF2 drugs for various NF1 ad NF2 tumors, bone dysplasia and learning disabilities. Most of these Awards have not yet concluded and it is still early to make firm conclusions about the impact of this program. However we already have some measures to suggest the program is a success as a catalyst program that gets new ideas off the ground. Of the 12 concluded Awards, 10 have continued progress, securing collectively $2,353,000 in further grant support – a return of 10 times the Foundation's initial investment of funds.  Eight awards have established relationships with a biotechnology or pharmaceutical company through the DDI project.  18 Awardees have already published or submitted a paper for publication that acknowledges DDI support, and probably the DDI’s the greatest accomplishment to date, results from one $11,000 DDI Award study have led to planning for a clinical trial. Dr. Oliver Hanemann (University of Plymouth) received a DDI Award to test Sorafenib in NF2 tumor explants tissue; the data was highly promising and Dr. Hanemann is now in line to receive UK government funding to take this forward to an NF2 clinical trial, a study that the Children’s Tumor Foundation hopes to collaborate on.

The DDI program will fund the most promising ideas, even those that are challenging and may be considered high risk. Such a project was funded this past summer to Dr. Jonathan Chernoff (Fox Chase Cancer Center) whose goal is to generate induced pluripotent stem (iPS) cells from skin of an adult mouse with an internal plexiform tumor, and transplant these into the bone marrow of the mouse. The goal is for these cells to generate healthy mast cells that will migrate to the tumor site and reduce tumor growth. This makes sense biologically since dysfunctional mast cells are believed to contribute to plexiform growth. This is a high risk project but one with enormous payoff if successful since it could be rapidly translated to humans without the ethical concerns of embryonic stem cells. We look forward to reporting on Dr. Chernoff’s DDI research in 2010.

The Foundation’s Neurofibromatosis Preclinical Consortium (NFPC) takes preclinical drug screening to a more advanced level. This 4-year, $5M effort unites six major US research centers each focused on a different NF1 or NF2 tumor mouse model:  Harvard Medical School (Dr. Andrea McClatchey – NF2 tumors and Dr. Karen Cichowski - MPNST), University of California San Francisco (Dr. Kevin Shannon – NF1 leukemias), Washington University (Dr. David Gutmann – optic glioma), House Ear Institute (Dr. Marco Giovannini – NF2 tumors) and Cincinnati Children’s Hospital Medical Center (Dr. Tim Cripe – plexiform neurofibroma). Together these sites test promising preclinical drug candidates in unison in multiple tumor models, to ensure that drugs are fully evaluated for potential clinical use in all NF tumor types. NFPC requires a significant commitment from industry partners, as we require quite substantial amounts of drugs as well as technical guidance and know-how. We were fortunate that the first collaborator/drug screen was with the major pharmaceutical company Novartis, to test their drug BEZ-235. With the Novartis collaboration near conclusion, NFPC has added new partners including another industry giant, Genentech, with other partners pending.