ORCID
https://orcid.org/0000-0001-7355-6411
Date of Award
2026
Document Type
Dissertation
Degree Name
Pharmaceutical Sciences (Ph.D.)
Department
Pharmaceutical Sciences
First Advisor
Vikas Dukhande
Second Advisor
Zhe-Sheng Chen
Third Advisor
Tanaji Talele
Abstract
Glioblastoma Multiforme (GBM) is a grade IV astrocytoma. GBM is the most prevalent primary malignant brain tumor, with a 5-year survival rate of ~7%. Over the decades, the median survival of GBM patients has remained unchanged at merely 12-18 months from diagnosis. The current treatment strategy for GBM includes surgery, chemotherapy with the standard of care drug temozolomide (TMZ), and radiation. Extensive research has been done in search of novel therapeutics for GBM, due to the high rate of chemoresistance to TMZ and tumor recurrence. Amongst the many reasons responsible for its highly aggressive and invasive nature is metabolic reprogramming in GBM, which assists in tumor growth. In our research, we aimed at targeting the metabolic reprogramming of cancer by an FDA-approved anti-epileptic drug, stiripentol (STP). STP has demonstrated its potential against GBM in recent studies, including our own; however, the precise mechanism of its anti-cancer activity remains unclear. Our research aimed to decipher the mechanistic insights into STP’s anti-tumor activity using a multi-omics approach encompassing transcriptomics and metabolomics. RNA seq revealed the differential expression of genes ALDH1A3, AOX1, TXNIP, CPA4 etc., whereas metabolomic analysis suggested the involvement of major metabolic pathways such as thiamine metabolism, phenylalanine metabolism, purine and pyrimidine metabolism, affected by STP. Metabolic alterations were validated by Seahorse metabolic assay and western blotting. Our data showed the increase in ROS levels as well as senescence-mediated decreased cellular proliferation in GBM cells. In this study, we also aimed to address the challenge of blood-brain barrier (BBB) permeation as well as overcoming the limitation of STP’s oral bioavailability by formulating a self-nanoemulsifying drug delivery system (STP-NE). Both STP and STP-NE were evaluated for their in vitro efficacy using GBM 3D spheroids and in vivo efficacy in a tumor xenograft model. Taken together, our data elucidated the anticancer mechanism of STP and highlighted its potential for GBM therapy. Further research is needed to develop a novel therapeutic for GBM targeting its metabolic reprogramming.
Recommended Citation
Yadav, Anjali, "MECHANISTIC PHARMACOLOGY AND PRECLINICAL RESEARCH OF STIRIPENTOL, A POTENTIAL THERAPEUTIC FOR GLIOBLASTOMA" (2026). Theses and Dissertations. 1022.
https://scholar.stjohns.edu/theses_dissertations/1022