Evaluating the role of SPAK and OSR1 kinases in glioblastoma chemotherapy resistance

Project Summary Glioblastoma (GBM) is the most devastating brain neoplasm with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, and chemotherapy, the disease recurs and is fatal. Given its public health importance, there is an unmet need for new treatment strategies to prolong patient survival while improving the quality of life. SPAK (SPS1-related

proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase) are stress-sensing kinases that phosphorylate and activate NKCC and KCC ion co-transporters which are key players in restoring intracellular Cl- and cell volume in response to cell stress. This is of importance because cell volume decrease and reduction of total intracellular ionic strength (via

Cl- and K+) are the earliest stimuli that lead to apoptosis. Cancer cells can counteract pro- apoptotic signals by using regulatory volume increase through SPAK/OSR1/NKCC1 activation. Therefore, these kinases can serve as a resistance mechanism to cell death. On the other hand, cell volume regulation is an essential mechanism for cell migration in the confined spaces in the

brain. Our preliminary data using genetic and pharmacological inhibition of SPAK/OSR1 shows that these kinases decrease GBM cell migration, proliferation and tumor growth in vivo and could serve as a mechanism of therapy resistance to chemoradiotherapy. However, SPAK/OSR1 function, mechanism, and therapeutic role in GBM remains unexplored. We hypothesize that

SPAK/OSR1 exerts oncogenic functions as a cell-stress resistance mechanism allowing cancer cells to survive hostile environments and enhance GBM malignancy. The goal of this proposal is to evaluate if SPAK/OSR1 serves as a mechanism of resistance to the standard of care. We will evaluate the therapeutic efficacy of SPAK/OSR1 inhibition using a novel small molecule inhibitor

in combination with chemo-radiotherapy and describe the role of SPAK/OSR1 in tumor resistance. Our long-term goal is to set the foundation for a research program that will study the relevance of the SPAK/OSR1 pathway in GBM progression identifying druggable signaling pathways that regulate GBM cell invasion and proliferation.