EVALUATING MOLECULAR INHIBITORS
PRECLINICAL RESEARCH IN NEURO-ONCOLOGY
TRANSLATIONAL NEURO-ONCOLOGY LABORATORIES (TNOL)
TESTING COMBINATION THERAPY IN BRAIN TUMOR TREATMENT
A major aspect of Dr. Kesari's lab research activities is in evaluating small molecular inhibitors of developmental pathways thought to be important in neural and cancer stem cells. In particular, the Notch pathway has been shown to be important in gliomas. Notch is a protein that was originally identified in fruit flies as a key player in the normal development of a range of blood cells. The protein was also found to be mutated in nearly 60% of patients with a specific subtype of pediatric leukemia. For it to be active, Notch requires the presence of a second protein called gamma-secretase. Because this second protein is linked to Alzheimer's disease, many drug companies already have gamma-secretase inhibitors on their shelves. Dr. Kesari has shown that a gamma-secretase inhibitor can stop the growth of glioma stem cells. Our preclinical studies are promising and provide the rationale of a Phase II trial of this protein in patients with recurrent malignant gliomas.
Most cancers that initially respond to treatment such as kinase inhibitors ultimately become drug resistant. Mechanism of drug resistance seems to involve the engagement of compensatory pathways, which normally regulate signal transduction homeostasis, allowing for dynamic signaling responses in different environmental circumstances. The discovery of such signaling plasticity highlights the importance of understanding signaling pathways from a 'systems' perspective, in order to determine which combination of targets might yield the desired biological outcome. This requires a combination of rational and screening approaches. In our laboratory we are investigating both approaches. By applying selective single agents and monitoring the compensatory signaling response, as well as applying mathematical models of signaling pathways based on quantitative phosphoproteomics data, we aim to reveal targetable key nodal points in the signaling circuits. Dr. Kesari is actively advocating collaborations with various companies to develop and test new drugs as well as various drug combinations. These preclinical tests have already set the basis for a second generation of clinical trials using combination therapy in patients. New drug targeting the developmental and cell death pathways of brain tumors are also being tested in combination with standard therapies (i.e. chemotherapy and radiation).
Another interesting area for drug development is the possibility to attack the cancer stem cells. There is an increasing body of evidence that brain tumors may arise from abnormal stem cells in the brain, and that these cells contribute to the recurrence and resistant of gliomas to current treatments. Dr. Kesari has already shown that Olig genes play a crucial role in allowing stem cells to become gliomas. We are now working on developing therapies directed against such genes. This may represent a novel way to treat malignant gliomas.
SANTOSH KESARI, MD, PhD