|Education||BS, University of Hawaii, Manoa|
Glioblastoma multiforme (GBM) is the most common and deadliest type of malignant primary brain tumors in adults. The current treatment for GBM patients, surgical resection followed by chemo-radiation therapy with alkylating agent, temozolomide, has not been successful in significantly improving clinical outcome over median survival time of 12 months. Therefore, a new, effective approach to therapeutically target this cancer is urgently needed. Receptor tyrosine kinases (RTKs) are frequently aberrant in GBM and have been the ‘low hanging fruit’ as targets for therapy. However, co-activation of multiple RTKs and tumor heterogeneity make it extremely hard for targeted therapy to be effective. These shortcomings could be circumvented by a druggable target that mediates pan-specific receptor clearance in GBM cells.
We recently made the unexpected discovery that the autism-associated gene SLC9A9 is up-regulated in a subset of glioblastoma where it is a driver of tumor growth and migration, and associated with poor patient survival and chemoradiation resistance. The gene encodes NHE9, an endosomal Na+/H+ exchanger that transports protons out of the vesicle lumen in exchange for cations, to finely tune endosomal pH. The pH of the endolysosomal system is known to be critical for growth factor receptor sorting and turnover.
The focus of my project is to study the role of NHE9 in membrane persistence of multiple RTKs and downstream oncogenic pathways in patient-derived brain tumor stem cells. I am investigating the regulation of stem cell-like phenotype by these RTKs, which is known to confer chemoradiational resistance. A related goal is to evaluate the effect of NHE9 on immune-suppression by modulating surface levels of immune-checkpoint molecules in GBM cells. Lastly, we will also evaluate PBAE nanoparticles coated with siRNA to selectively silence NHE9 in brain tumor cells. As an alternative, we will assess the efficacy of acidifying nanoparticles to correct endosomal pH. Taken together, we propose a combined mechanistic and translational approach towards a novel target of chemoradiation resistance in glioblastoma.