A central function of p53 is to promote cell cycle exit and differentiation. Progenitor cells that drive organogenesis and tissue repair take a calculated risk to defeat p53 functions so as to sustain the replication competent state. Under auspices of this grant we have shown how neural progenitors occasionally lose this gamble. Our findings may have practical overtones for the treatment of high-grade glioma in humans. Put briefly we have learned: (1) That the bHLH transcription factor OLIG2 opposes p53 responses to genotoxic damage in both normal and malignant neural progenitors (2) that that the p53-supressive function of OLIG2 requires phosphorylation of an amino terminal triple serine motif and (3) that this triple serine motif of OLIG2 is phosphorylated in high-grade human gliomas. Our recent observations suggest that small molecule inhibitors of the OLIG2 protein kinase(s) could serve as targeted therapeutics for high-grade gliomas - either as stand alone modalities or (more likely) as adjuvants to radiotherapy and genotoxic drugs. The objectives of our study plan in this renewal application are to use human clinical materials to test this hypothesis (aims one and two) and to use genetically engineered murine neural progenitors to identify the critical OLIG2 kinase(s) (aim three). The PI and Co PI of this application have complementary backgrounds/skill sets and a tangible track record of productive interactions. The combined brain tumor tissue banking cores of Dana-Farber and UCSF can provide clinical sample sets that are statistically powered to address the issues raised in aims one and two.
For aim three, we have devised robust, high throughput chemical and genetic screens for the OLIG2 protein kinase(s). These screens complement each other with respect to their strengths and weaknesses. Accordingly, we believe that odds of success are favorable.

Public Health Relevance

High-grade gliomas (WHO grades III and IV) are the third leading cause of cancer-related death among middle-aged men and the fourth leading cause of death for women between 15-34 years of age. As detailed in our study plan, there is a plausible argument to be made that small molecule inhibitors of OLIG2 phosphorylation could serve as targeted therapeutics for roughly 75% of adult high-grade gliomas - either as stand alone modalities or (more likely) as adjuvants to radiotherapy and genotoxic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057727-08
Application #
8672697
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2006-12-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$431,962
Indirect Cost
$107,222
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Silbereis, John C; Nobuta, Hiroko; Tsai, Hui-Hsin et al. (2014) Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 81:574-87
Meijer, Dimphna H; Sun, Yu; Liu, Tao et al. (2014) An amino terminal phosphorylation motif regulates intranuclear compartmentalization of Olig2 in neural progenitor cells. J Neurosci 34:8507-18
Sun, Yu; Meijer, Dimphna H; Alberta, John A et al. (2011) Phosphorylation state of Olig2 regulates proliferation of neural progenitors. Neuron 69:906-17
Mehta, Shwetal; Huillard, Emmanuelle; Kesari, Santosh et al. (2011) The central nervous system-restricted transcription factor Olig2 opposes p53 responses to genotoxic damage in neural progenitors and malignant glioma. Cancer Cell 19:359-71
Stiles, Charles D; Rowitch, David H (2008) Glioma stem cells: a midterm exam. Neuron 58:832-46