Page 35 - The Hormel Institute 2024 Annual Report

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Glioblastoma (GBM) is the most aggres- sive primary brain tumor and is virtually incurable because most anticancer agents
cannot cross the blood-brain barrier (BBB).
To date, after surgery, temozolomide (TMZ) and radiation (RT) are the only key components of standard therapy to debulk the tumor within newly diagnosed GBM patients. However, the impact of these therapies on the overall survival of GBM patients is limited by pre-existing or acquired resistance.
A better understanding of the mechanisms affecting sensitivity to TMZ and RT may provide critical insight toward designing more effective GBM therapies.
Response to TMZ therapy is mechanistically linked to the expression of a DNA repair protein called O6-methylguanine-DNA-methyltransfer- ase (MGMT) and is regulated epigenetically by promoter hypermethylation. Lack of promoter methylation is linked to high-level MGMT expres- sion and poor survival compared to tumors with suppressed MGMT expression and promoter hypermethylation.
But not all GBM patients with MGMT-hypermeth- ylated tumors respond to TMZ, and resistance develops rapidly, leading to recurrence and death, often within 3 years of diagnosis. Thus, the overall goal of my lab is to identify novel
gene targets that modulate TMZ sensitivity and use targets for developing TMZ-sensitizing therapies for GBM patients.
We identified ~600 druggable modulators of TMZ sensitivity in GBM cells. Our work this past year focused on continuing to investigate the role of a specific protein complex in regulating key genes involved in DNA damage repair.
Also, we characterized another target EXPORTIN 1 (XPO1), a key member of the nuclear-cytoplas- mic transport pathway. XPO1 inhibitor Selinexor is an FDA-approved medicine for refractive multiple myeloma, and because of the potential to cross the BBB, it is being evaluated for GBM therapy in combination with TMZ and RT.
We have identified an interesting mechanism regulating the Selinexor/TMZ sensitivity in GBM. Some of these findings were accepted for plat- form presentation at a conference, and we are preparing manuscripts reporting our findings on the protein complex and Selinexor.
We also started validating an additional 220 of the 603 candidate druggable modulators of TMZ sensitivity that were identified through RNAi screening. Through this secondary validation effort, we narrowed down the list to 40 drugga- ble candidate genes, and characterization of the best candidates is in progress.