AACR Anna D. Barker Fellowships in Basic Cancer Research foster basic research by scientists at the beginning of their careers in the cancer field. They are open to postdoctoral and clinical research fellows at an academic facility, teaching hospital or research institution who will be in the first, second or third year of their postdoctoral training at the start of the fellowship term. Fellowships support the salary and benefits of the fellow, with partial funds permitted to be designated to direct research expenses.
2012 GRANTEE
Amélie Griveau, Ph.D.
Postdoctoral Fellow, University of California, San Francisco, CA
Phosphorylated-Olig2 Biochemical Function in Pediatric Glioma
"High-grade gliomas are a leading cause of solid tumor-related mortality in children. However, the development of rational therapies for treating those tumors has been limited by poor information regarding the cell of origin and the relevant underlying genetic alterations. Several recent reports now indicate that mutations occurring in pediatric glioma, as well as their cells-of-origin, are remarkably different than that seen in adult gliomas (GBM), even in tumors with very similar histology. The Pediatric Cancer Genome Project found that an important proportion of glioblastomas arise in the brain stem in children, but not in adults and that about 80 percent of these tumors present the same missense mutation, a genetic signature which will be used for the development of new therapies. In addition, the Pediatric Brain Tumor Institute at UCSF has found that BRAF activating mutations, associated with deletion of the tumor suppressor gene CDKN2a (Ink4a-Arf) are found in about 15 percent of pediatric gliomas (grade II-IV), compared to only about 3 percent of adult GBMs. Further, we have generated a faithful genetic mouse model in which concomitant activation of BRAFV600E and homozygous deletion of Ink4a-Arf in neural progenitors leads to the generation of pediatric high-grade glioma. In addition, we were able to show that pharmacological inhibition of the BRAF pathway in combination with inhibitors of the CDKN2a pathway led to promising regression of the tumor.
"The bHLH transcription factor Olig2 is required for normal oligodendrocyte development and it is expressed in 100 percent of human pediatric and adult high-grade gliomas. Within glioma, most proliferating tumor cells show Olig2 expression and we have shown a genetic requirement for Olig2 in an adult mouse model of glioma. Recently, we found that Olig2 function seems to depend on its phosphorylation state: phosphorylated-Olig2 promotes proliferation of adult glioma progenitors, in part by antagonizing the tumor suppressor protein p53. My preliminary data show that activation of BRAFV600E in glial progenitors promotes oligodendrocyte proliferation. In this project, I want, first, to determine whether Olig2 phosphorylation is required in pediatric glioma. I will employ newly generated knock in transgenic mice with wild-type Olig2 and phospho-null mutants and a downstream FACS selectable tag to harvest the cells. In a second time, I will characterize the critical protein partners of phospho-Olig2 by using these new alleles. I will investigate protein partners of phosphorylated and non-phosphorylated Olig2 in the context of glioma and normal oligodendrocyte development, an exciting step that should provide insight into the co-factors that underlie pediatric gliomagenesis.
"I am very grateful for having been awarded by the Anna D. Barker Fellowship in Basic Cancer Research from the American Association for Cancer Research. This fellowship will give me the opportunity to develop this project and to understand new mechanisms implicated in tumor formation. Presently, there is no effective targeted therapy to treat pediatric patients with high-grade glioma. This work could have practical overtones for designing new treatments. A high specificity is needed to target glioma-specific roles of Olig2 and avoid global effects on oligodendrocyte development. Post-translational modifications of Olig2 and its co-factors provide additional avenues for possible therapy of glioma by targeting these processes."
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