Glioblastomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority (~75%) of these tumors. Resistance to genotoxic modalities in p53-intact gliomas has been attributed to attenuation of p53 functions by other mutations within a p53 signaling axis that includes CDKN2A(p14 Arf), MDM2 and ATM. In preliminary studies, we have generated an alternative and potentially actionable resolution to the p53 paradox. Put briefly, we have shown that the gliogenic transcription factor OLIG2 suppresses p53-mediated responses to genotoxic damage in glioblastoma cells. Against this backdrop, the broad objective of studies proposed in this SPORE project is to use clinical materials to test the hypothesis that small molecule inhibitors of OLIG2 could serve as targeted therapeutics for glioblastoma - either as stand alone modalities or (more likely) as adjuvants to radiotherapy and genotoxic drugs. This hypothesis makes four testable predictions: Our first specific aim is to test the prediction that current standard of care (radiation and Temozolomide) actually enriches for OLIG2-positive cells within p53-positive glioblastomas. Our second specific aim is to test the prediction that one current class of radiosensifizing drugs - the HDAC inhibitors - actually work by suppressing OLIG2 expression in cancer patients. Our third specific aim is to test the prediction that genetic suppression of OL1G2 can sensitize p53-positive human gliomas to radiotherapy in vivo. Our fourth specific aim is to test the prediction that shRNA-mediated knockdown of genes essential to OLIG2 function (e.g. HDACs) will be synthetic lethal to irradiation in p53 positive gliomas. The basic scientist on this project (CD Stiles, PhD) is a molecular biologist and the clinical investigator (JS Loeffler) is a radiation oncologist. Dr Stiles and his students initially cloned the OLIG genes and defined their biological functions in brain development and malignant glioma. Dr Loeffier is a leader in the field of brain tumor irradiation with a special interest in glioblastomas. Together they have the skill sets required for successful completion ofthe study plan. The work they propose will be supported by dedicated SPORE core facilities for Pathology and Biostatistics. If the work described here supports the view that OLIG2 is a viable target for glioma therapeutics, clinical trials of OLIG2 antagonists (e.g. HDAC inhibitors) as an adjuvant to radiotherapy can be initiated within a five-year period of time.

Public Health Relevance

Glioblastomas 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. In the fullness of time, the work we propose could change the standard of care for these tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Program Officer
Arnold, Julia T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Zhao, Yingchao; Liu, Pinan; Zhang, Na et al. (2018) Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models. Proc Natl Acad Sci U S A 115:E2077-E2084
Bian, X; Gao, J; Luo, F et al. (2018) PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy. Oncogene 37:341-351
McBrayer, Samuel K; Mayers, Jared R; DiNatale, Gabriel J et al. (2018) Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 175:101-116.e25
McKenney, Anna Sophia; Lau, Allison N; Somasundara, Amritha Varshini Hanasoge et al. (2018) JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Invest 128:789-804
Shankar, Ganesh M; Kirtane, Ameya R; Miller, Julie J et al. (2018) Genotype-targeted local therapy of glioma. Proc Natl Acad Sci U S A 115:E8388-E8394
Arvanitis, Costas D; Askoxylakis, Vasileios; Guo, Yutong et al. (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc Natl Acad Sci U S A 115:E8717-E8726
Li, Ben B; Qian, Changli; Roberts, Thomas M et al. (2018) Targeted Profiling of RNA Translation. Curr Protoc Mol Biol :e71
Nowosielski, Martha; Wen, Patrick Y (2018) Imaging Criteria in Neuro-oncology. Semin Neurol 38:24-31
Li, Ben B; Qian, Changli; Gameiro, Paulo A et al. (2018) Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins. Proc Natl Acad Sci U S A 115:E9325-E9332
Khandekar, Melin J; Jain, Rakesh (2018) Smooth sailing for immunotherapy for unresectable stage III non-small cell lung cancer: the PACIFIC study. Transl Cancer Res 7:S16-S20

Showing the most recent 10 out of 84 publications