Rinato Hashizume, Ph.D has been working on understanding DIPG for some time. His lab, part of the Brain Tumor Research Center at USCF, is specifically interested in understanding tumor molecular biology, developing animal models and using these models in novel approaches to fight pediatric brain tumors. Here are some specific DIPG project that this lab has undertaken:
1) Diffuse Intrinsic Pontine Glioma Xenograft Panel- One of the significant hurdles for DIPG research has been the lack of animal models to be able to preform preclinical testing for DIPGs. This lab has established tumorigenic DIPG cell lines from human biopsy samples. These cell have been injected into animal brainstem to create a new animal model.
2)Targeting PDGFRA- A Key Pathway for Brainstem Tumorigenesis and Effective Therpeutic Strategy- It has been found that approximately 29-36% of DIPGs have a genetic alteration called PDGFRA amplification. In mice, it has been found that increased PDGFR signaling of the 4th ventricle subventricular zone nestin+ cells cause gliomas. It has also been found that the population of nestin+ cells peak about the same time as the incidence of DIPG in kids.
This labs has found that DIPG have increased PDGFRA and RB but do not have a tumor suppressor called p16NK4A. In addition, the brainstem model was found to have both Nestin ceells and Oligo2 cells. It is hypothesized that these cells could present a pool from where brainstem gliomas originate. The Oligo 2 cells seem to make PDGFRA which might indicated these cells keep the gliomas growing.
The Hashizume lab is investigating the consequences of these alternations in mice.
3) Intranasal Delivery- Another hurdle for DIPG treatment has been the difficulty in getting agents to the tumor because of the blood brain barrier. This lab is working to test an alternative delivery system using the nose. There are alot of advantages to intranasal delivery including:
-avoidance of the first pass effect of the liver on intravenous administration,
-reduction of system side effects, and
-more convenient self administration.
This lab has shown the intranasal delivery of GRN163 has doubled survival in rats. The lab is now working on other formulation with liposomes to try to improve on these results.
Funding for at least part of this work has come from the Pediatric Brain Tumor Foundation of the US which has been a long time supporter of the pediatric brain tumor work at UCSF through a 1.3 million dollar PBTFUS Institute Award. This award included specific work on brainstem gliomas.
Hashizume DIPG Publications:
Telomerase inhibitors for the treatment of brain tumors and the potential of intranasal delivery.
New therapeutic approach for brain tumors:Intranasal delivery of telomerase inhibitor GRN 163.
Free Full Text- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613813/
An experimental xenograft mouse model of diffuse pontine glioma designed for therapeutic testing.
A human brainstem glioma xenograft model enabled for bioluminenscence imaging.
Free Full Text- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808534/
PBTFUS Institute Program- http://www.curethekids.org/medcomm/institutes/