# Leveraging Gα12 signaling to treat glioblastoma

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $79,000

## Abstract

Abstract
Glioblastoma multiforme, one of the most aggressive primary brain tumors, has a dismal
prognosis despite treatment advancements in the past decades. Low patient survival is driven by
disease recurrency after a period of remission. GBM is a highly invasive tumor, which makes
surgical recession difficult. G-protein coupled receptors are increasingly recognized for their ability
to regulate tumor growth. Many of these receptors signal through their coupling to the alpha
subunit of the heterotrimeric G-protein Ga12. In silico interrogation of GBM in The Cancer
Genome Atlas reveals marked upregulation of GNA12, the gene encoding G⍺12, concomitant
with overexpression of G-protein coupled receptors (GPCRs) that signal through this G-protein.
We recently determined that targeting G⍺12 in human glioma stem cells (GSCs) attenuates tumor
cell self-renewal, expression of stem cell genes, and invasion. Concordantly G⍺12 knockdown
(KD) reduced invasion of tumors from orthotopically engrafted GSC cells in vivo. Reciprocally,
chemogenetic activation of G⍺12 increased invasion. G⍺12 KD tumors assessed by RNA seq
showed reduced expression of cell adhesion and migration genes, as well as increased
expression of proneural genes. The observed changes in migratory behavior and gene expression
suggest that G⍺12 signaling promotes a proneural-to-mesenchymal transition. The evidence that
G⍺12 signaling regulates transcriptional programs for stemness and invasion of GSCs identifies
this as a potential signaling node for therapeutic intervention. Surgery followed by radiation
therapy is the standard of care for GBM. Decreases in stemness and invasiveness, associated
with a more proneural state, would be predictive of improved sensitivity to radiation therapy which
could in turn ameliorate disease recurrence and damage to healthy brain tissue. Our short-term
goal is to provide evidence for enhanced GSC susceptibility to radiation treatment in cells lacking
G⍺12 signaling. We will use single dose irradiation of GSCs in cell culture and in tumor bearing
mice using image-guided irradiation. Our innovative approach leverages the newly discovered
role of G⍺12 on tumor growth and invasiveness to improve GBM treatment. The ability to evaluate
radiosensitization, elicited by blockade of G⍺12 signals, in human patient derived glioma cells,
using image-guided irradiation is consistent with precision medicine approaches. Thus, our
findings could impact radiation treatment of resistant tumors and improve GBM patient survival.
If successful, our studies will be the first to demonstrate the benefit of targeting G⍺12 signaling in
association with radiation to treat GBM and will implicate G⍺12-coupled receptors and their
transcriptionally regulated gene targets as potential points of therapeutic intervention.

## Key facts

- **NIH application ID:** 10649241
- **Project number:** 1R03NS131822-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Olga Chaim
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $79,000
- **Award type:** 1
- **Project period:** 2023-04-01 → 2024-03-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10649241

## Citation

> US National Institutes of Health, RePORTER application 10649241, Leveraging Gα12 signaling to treat glioblastoma (1R03NS131822-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10649241. Licensed CC0.

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