Page 40 - Hormel Institute Annual Report 2021-22

Gasper Kitange, PhD
“Glioblastoma (GBM) is the most aggressive primary brain tumor and is an incurable disease. GBM fatality is largely due to limited therapeutic options related to blood brain barrier (BBB) and the resistance to current therapy. Therefore, understanding the resistance mechanisms and discovery
of novel drug targets is critical step toward
finding better GBM therapy.”
Gasper Kitange
Lab research activities:
https://www.hi.umn.edu/research/research- sections/cancer-therapy-resistance- and-drug-target-discovery-program/
ORCID iD: https://orcid.org/0000-0002- 0548-1312
40 | THE HORMEL INSTITUTE // Cancer Drug Resistance and
Drug Targets Discovery
ASSOCIATE PROFESSOR
UNIVERSITY OF MINNESOTA
My laboratory uses high throughput approach to identify novel molecular targets for therapy, as single agents or
in combination with temozolomide (TMZ) and/ or radiation. In addition, my lab investigates the mechanisms of resistance to therapy, with special focus on defining the epigenetic modu- lators of resistance to TMZ. These studies are conducted in vitro and in vivo.
Role of RBBP4/p300 complex on the recovery from therapy induced DNA damage.
This project is based on our recent findings
that RBBP4/300 complex controls transcription of multiple DNA repair genes involved in the homologous recombination pathway. This proj- ect is focused on elucidating the mechanisms by which this complex controls these DNA repair genes and how this may impact the ability
of GBM cells to recover from temozolomide- induced DNA double strand breaks. The overar- ching goal is to target this complex for sensitiz- ing temozolomide and/or radiation in GBM.
Investigating the role of nucleocytoplas- mic transport on temozolomide sensitiv- ity in GBM.
Our genome wide screening identified KPNA1 and XPO1, the key proteins involved in nucle- ocytoplasmic cargo transport, as modulators
of TMZ sensitivity in GBM cells. This project is focused on further understanding why sensitivi- ty of GBM cells to XPO1 inhibitor Selinexor alone and in combination with TMZ is influenced by MGMT expression status and elucidating how Selinexor induces MGMT expression in unmeth- ylated GBM cells. The findings from this project will provide an insight on how to design more effective Selinexor-based therapy as a single agent or in combination with TMZ and/or
other agents.
Identification and validation of novel TMZ-sensitizing druggable targets.
The overall goal of this project is to identify novel targets for GBM therapy. To that end, we have identified over six-hundreds TMZ-sensitizing druggable candidates, and we have used siRNA to validate a total of 215 candidates. From
these validation experiments, we have identified few most interesting candidates, which we are currently testing in combination with TMZ using biochemical and pharmacologic inhibition.