Date of Award
MS in Science
Glioblastoma multiforme (GBM) is a grade IV malignant glioma. It is a highly proliferative form of brain tumor with 5-year survival rate ~ 5% indicating a high mortality rate. Current treatment strategies for GBM include surgery, radiation, and chemotherapy. Surgical resection is challenging due to vital function of brain and as GBM often metastasizes in different brain regions. Additionally, development of resistance against the standard of care drug temozolomide (TMZ) is a major challenge in GBM management. GBM is also shielded with the blood brain barrier (BBB) which prevents the entry of several drugs. Therefore, a new drug must overcome the problems of crossing the blood brain barrier (BBB) and chemoresistance. Although several attempts at developing a novel therapy for GBM have been carried out, most clinical trials did not result in survival benefits for patients. We discovered an FDA-approved drug stiripentol (STP) in our screening of brain permeable metabolic inhibitors. STP is used for Dravet syndrome (a rare form of epilepsy). STP is a safe drug and surpasses the BBB made us to pursue it for the potential treatment of GBM. STP was tested for cytotoxicity in U87 and U138 astrocytoma cells and was found effective for GBM. Thereafter, various cell biology assays were used to assess the effect of STP on cell proliferation, migration, clonogenic survival, cell cycle. In addition, mechanism of cell death was probed upon STP treatment in U87 cells. Next, effect of STP on U87 3D spheroid assay was performed. Assays were also performed to determine synergy potential for STP and TMZ in U87 cells. Our results indicate that STP can be an effective GBM therapeutic that enhances the effects of TMZ in U87 cells. We are currently exploring the structure-activity relationship of STP scaffold by derivatization strategy to achieve more potent brain-permeable compounds. Our future work will elucidate mechanistic basis of STP’s effects on GBM cells and preclinical potential of STP by tumor xenograft study.
Yadav, Anjali, "REPURPOSING AN ANTI-EPILEPTIC DRUG FOR THE TREATMENT OF GLIOBLASTOMA" (2022). Theses and Dissertations. 571.
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