TRANSLATIONAL NEURO-ONCOLOGY LABORATORIES (TNOL)

SANTOSH  KESARI,  MD, PhD

Using a variety of molecular, cellular, and genetic techniques, we are studying the function of proteins that regulate the activity of genes in neural and tumor stem cells. We are interested in the role of OLIG and other transcription factors in the biology of gliomas. We are also studying tyrosine kinase receptors that are key regulators of proliferation and growth of gliomas.

By isolating glioma stem cells from fresh human surgical tissue and culturing in vitro and in vivo in mice we study the unique molecular and genetic biology of these cells in relation to the whole tumor.

Dr. Kesari and colleagues have shown that the same genetic regulator that triggers growth of stem cells during brain development, Olig2 (a transcription factor), also plays a central role in the development of malignant gliomas from glioma cancer stem cells. Olig2 is activated in the stem and progenitor cells found in the tumors. In a mouse model of malignant glioma, they found that taking away Olig2 stopped tumor formation in 91% of the animals. Their analysis of the role of Olig2 gene in both tumor cells and normal neural stem cells revealed that it plays a key role in enabling cell growth.  Dr. Kesari's findings identify Olig2 as an important candidate for antitumor therapeutics. Further studies are ongoing to unravel the mechanism of Olig2's function in glioma stem cells and screening drugs that will block this process with eventual goal of killing glioma stem cells.

OLIG and Other Transcription Factors, and Tyrosine Kinase Receptors in the Pathogenesis of Glioma

 MOLECULAR SIGNALLING  INITIATIVE

Liposomal encapsulation is a technique that can be used effectively to deliver chemotherapy to tumors at effective concentrations. We have developed a patented technology for highly efficient encapsulation and are using it to package various targeted therapeutic agents for glioblastoma. We recently published a study where we encapsulate a highly potent multi-kinase inhibitor, staurosporine that has high activity against many chemotherapy-resistant tumors.

 NANOTECHNOLOGY INITIATIVE

Astrocytes stained with anti-GFAP PE-labeled antibody (red); neurons stained with anti-NeuN AlexaFluor488-labeled antibody (green). Double staining was performed by immunohistochemistry on a coronal section from mouse brain harvested 15 days after tumor cell implantation.

Peritumoral Reactive Astrocytes

As part of the basic research in our laboratory, we are focusing on identifying the exact role of tumor metabolism and how this can be used to treat cancer. Tumors have high rate of metabolism due to the rapidly growing tumor cell population. This means a high rate of glucose utilization and mitochondrial function. In order to understand the role of tumor metabolism and to help design new treatment strategies, we are focusing on an important mitochondrial protein, called p32. We are exploring the role of this protein in glioblastoma and its effect on tumor growth and invasiveness.

 TUMOR METABOLISM INITIATIVE

BASIC SCIENCE RESEARCH  IN NEURO-ONCOLOGY