Page 40 - Hormel Report 2023
P. 40
Gasper Kitange, MD, PhD
“Glioblastoma is the most common and aggressive primary brain tumor. The median survival rate of glioblastoma patients is ~15 months, and less than 5% of patients survive to 5-years after the initial diagnosis. Glioblastoma fatality is largely due to resistance to
therapy driven by unknown mechanisms.”
Gasper Kitange
40 | THE HORMEL INSTITUTE // Cancer Drug Resistance and
Drug Targets Discovery
ASSOCIATE PROFESSOR
UNIVERSITY OF MINNESOTA
My lab focuses on research aimed at understanding the mechanisms that modulate primary and secondary
resistance to therapy in glioblastoma, particularly to temozolomid. To that end, we utilize high throughput whole genome screening to identify modifiers of temozolomide sensitivity using shRNA or CRISPR/Cas9 libraries. The candidate modifiers of temozolomide are validated in custom made secondary siRNA libraries and the best candidates are further characterized using shRNA, and the effect on sensitivity is evaluated in vitro and in vivo.
Epigenetic Regulation of Therapy-Induced DNA Damage in Glioblastoma.
My lab found that the chromatin modifier RBBP4 protein is a negative regulator of temozolomide sensitivity, and this function requires interaction with p300 histone acetyltransferase to form
RBBP4/p300 complex. My lab is the first to report that RBBP4/p300 complex is present in glioblastoma cells and demonstrated that this complex controls therapy sensitivity through regulation of a cascade of genes involved in the repair of DNA damage. The ongoing work on this project is aimed at mechanistically linking RBBP4/p300 with the epigenetic regulation of six genes involved in the homologous recombi- nation pathway.
Discovery and Characterization of Novel Molecular Targets for Sensitizing Therapy in Glioblastoma.
We have identified ~600 druggable modifiers of temozolomide sensitivity. This project focuses on validating these targets through secondary siRNA screening followed by biochemical and pharmacological characterization of the best candidates in vivo and in vitro.
