# Investigating mechanisms of kinase-mediated cell migration in aggressive glioblastoma

> **NIH NIH F32** · YALE UNIVERSITY · 2020 · $65,310

## Abstract

Project Summary – Mohler
Glioblastoma multiforme (GBM) is the deadliest brain tumor in adults, characterized by rapid progression and
poor prognosis due to its highly proliferative and invasive nature. GBM is dynamically heterogeneous with a
complex set of inputs ultimately determining a set of outputs (phenotypes) related to cell survival, proliferation,
and invasive migration. As a whole, the goals of this project are structured to provide insight into mechanisms of
glioblastoma cell migration. The approach is centered on assessing the contributions of underexplored kinase
regulatory networks to the phenotypic switch of cancer cells from proliferative to migratory states, underlying
aggressive disease progression. As the most abundant post-translational modifications in eukaryotic signaling
pathways, protein phosphorylation occupies a central role in regulatory networks and the maintenance of cellular
homeostasis, yet their roles in the mediation of cell migration are poorly understood. It has recently been shown
that GBM cells can use normal physiological processes for cell migration, such as exploiting ion channels like
NKCC1, to promote motility. The Ste20-family kinase SPS1-related proline/alanine-rich kinase (SPAK) relays
changes in cell volume to cation-chloride cotransporters (NKCCs and KCCs) to maintain cellular homeostasis
and control cell migration. Although previous reports have highlighted the importance of SPAK kinase as a
potential therapeutic target for the treatment of GBM, the inability to produce high yields of physiologically
phosphorylated kinase, until now, impeded this progress. Leveraging recent advances in orthogonal translation
systems and mass spectrometry from the Rinehart lab enables the implementation of a robust pipeline for the
identification and validation of lead inhibitor compounds which target physiologically phosphorylated, active
SPAK kinase. The impact of candidate SPAK inhibitors on the migration and physiology of GBM cells will be
assessed using a microfluidics based 1D cell migration assays. In parallel, the direct interactions and impacts of
candidate inhibitor compounds with the GBM proteome will defined using quantitative mass spectrometry
techniques. Overall, characterization of small molecule inhibitor compounds identified from this pipeline will
provide important mechanistic insight into the role of kinase networks in the regulation of cancer cell migration,
expanding potential applications to the broader scope of cancer biology.

## Key facts

- **NIH application ID:** 9968178
- **Project number:** 5F32CA224946-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kyle P. Mohler
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968178

## Citation

> US National Institutes of Health, RePORTER application 9968178, Investigating mechanisms of kinase-mediated cell migration in aggressive glioblastoma (5F32CA224946-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9968178. Licensed CC0.

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