"I believe that the Distinguished Scientist Award will be vital to the performance of this research, to my career enrichment, and to the development of a novel therapeutic target for malignant gliomas to ultimately benefit our patients."
- Dr. Santosh Kesari
- Chair, Department of Translational Neuro-Oncology and Neurotherapeutics, 2015-present
- Professor of Neurosciences, John Wayne Cancer Institute, 2015-present
- Director of Neuro-Oncology, Providence Saint John’s Health Center, 2015-present
- Member, Los Angeles Biomedical Research Institute, 2015-present
- Adjunct Professor in Radiation Medicine and Applied Sciences, UC San Diego, 2013-2015
- Professor in Neurosciences, UC San Diego, 2013-2015
- Adjunct Professor, Graduate School of Public Health, San Diego State University, 2013-2015
- Associate Professor in Neurosciences, UC San Diego, 2009-2013
- Visiting Associate Professor in Neurology, Harvard Medical School, 2009-2011
- Assistant Professor in Neurology, Harvard Medical School, 2007-2009
- Instructor in Neurology, Harvard Medical School, 2003-2007
About DSA-Funded Research
Glioblastoma (GBM) is the most lethal brain cancer that is notoriously resistant to standard treatments. A small population of CD133 (a stem cell marker) positive GBM stem cells has been shown to embody the tumorigenic potential. The lack of durable responses suggests that current treatments may not adequately target these stem cells.
The goal of this proposal is to elucidate the role of OLIG2 (a developmentally regulated transcription factor) in human GBM stem cells with the aim of discovering a new target(s) for the treatment of this devastating cancer. Our preliminary studies show that 1) OLIG2 is required for GBM formation in a mouse glioma model, 2) OLIG2 is expressed in human GBM stem cells, and 3) OLIG2 regulates the P53-inducible cell cycle inhibitor gene P21. The overall objective is to test the hypothesis that OLIG2 opposes P53 function(s) in GBM stem cells.
- Aim 1 is to test the prediction that suppression of OLIG2-deficient GBM stem cells wll stimulate the expression of P21 in primary GBM stem cells and suppress the growth of tumors.
- Aim 2 is to test the prediction that loss of P21 will rescue the growth of OLIG2-deficient GBM stem cells.
- Aim 3 is to test the prediction that other identified P53-inducible genes are also suppressed by OLIG2.
This proposal will identify and validate genes along a novel "OLIG2: P53 signaling axis" that may account for the resistance of GBMs to radiotherapy and chemotherapy. This will pave the way for the development of more effective therapies for GBM.
"I feel that Santosh is an outstanding and promising young investigator in the field of Neuro-Oncology and already shows evidence that he will become a leading player in the years to come. He is the closest thing to a certain bet for academic success that one can imagine."
Martin A. Samuels, M.D.
Chairman, Department of Neurology, Brigham and Women's Hospital
/Professor of Neurology, Harvard Medical School
"Dr. Kesari is one of the rising stars in neuro-oncology with the rare potential to make important advances in the laboratory and translating these advances into the clinic."
Patrick Wen, M.D.
Dana-Farber/Brigham and Women's Hospital
- The central nervous system-restricted transcription factor Olig2 opposes p53 responses to genotoxic damage in neural progenitors and malignant glioma. View here, Mehta S, Huillard E, Kesari S, Maire CL, Golebiowski D, Harrington EP, Alberta JA, Kane MF, Theisen M, Ligon KL, Rowitch DH, Stiles CD. Cancer Cell. 2011 Mar 8;19(3):359-71. doi: 10.1016/j.ccr.2011.01.035.
- Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. View here Ligon KL, Huillard E, Mehta S, Kesari S, Liu H, Alberta JA, Bachoo RM, Kane M, Louis DN, Depinho RA, Anderson DJ, Stiles CD, Rowitch DH. Neuron. 2007 Feb 15;53(4):503-17.
- Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma. Link here, Tsigelny IF1,2,3, Mukthavaram R3, Kouznetsova VL2,3, Chao Y3, Babic I3, Nurmemmedov E4, Pastorino S3, Jiang P3, Calligaris D5, Agar N5, Scadeng M6, Pingle SC3, Wrasidlo W1,3, Makale MT3, Kesari S1,3,7. Oncotarget. 2015 Oct 30. doi: 10.18632/oncotarget.5633.
- Novel small molecule inhibitors of the OLIG2 transcription factor: promising new therapeutics for glioblastoma. Link here, Alton G1, Kesari S2. Future Oncol. 2016;12(8):1001-4. doi: 10.2217/fon-2015-0078. Epub 2016 Feb 12.
- Molecular mechanisms of OLIG2 transcription factor in brain cancer. Link here, Tsigelny IF1,2,3, Kouznetsova VL2,3, Lian N4, Kesari S5,6.Oncotarget. 2016 Jul 16. doi: 10.18632/oncotarget.10628.