Aquaporins and Ion Channels as Dual Targets in the Design of Novel Glioblastoma Therapeutics to Limit Invasiveness

SIMPLE SUMMARY: Glioblastoma is a devastating brain tumor that, even with the best available treatments, leads to death for most patients in less than two years after diagnosis, due primarily to its highly invasive nature. Certain membrane signaling proteins (ion channels and water channels) that contribute to cell migration are known to increase in abundance as glioblastoma severity worsens, but have not been explored as possible therapeutic targets. This review evaluates the novel proposal that clinical value might be achieved by simultaneously targeting selected combinations of membrane proteins which show patterns of co-occurrence unique to glioblastoma subtypes. The dual targeting of signaling pathways with pharmacological blockers might exploit cell-specific vulnerabilities in glioblastoma while reducing off-target consequences on normal neurons and glial cells. The optimization of target selection and doses could launch innovative methods to control the spreading of pathological brain tumors, enhancing the success of primary treatments (surgery, radio- and chemotherapy) which comprise current best practice. ABSTRACT: Current therapies for Glioblastoma multiforme (GBM) focus on eradicating primary tumors using radiotherapy, chemotherapy and surgical resection, but have limited success in controlling the invasive spread of glioma cells into a healthy brain, the major factor driving short survival times for patients post-diagnosis. Transcriptomic analyses of GBM biopsies reveal clusters of membrane signaling proteins that in combination serve as robust prognostic indicators, including aquaporins and ion channels, which are upregulated in GBM and implicated in enhanced glioblastoma motility. Accumulating evidence supports our proposal that the concurrent pharmacological targeting of selected subclasses of aquaporins and ion channels could impede glioblastoma invasiveness by impairing key cellular motility pathways. Optimal sets of channels to be selected as targets for combined therapies could be tailored to the GBM cancer subtype, taking advantage of differences in patterns of expression between channels that are characteristic of GBM subtypes, as well as distinguishing them from non-cancerous brain cells such as neurons and glia. Focusing agents on a unique channel fingerprint in GBM would further allow combined agents to be administered at near threshold doses, potentially reducing off-target toxicity. Adjunct therapies which confine GBM tumors to their primary sites during clinical treatments would offer profound advantages for treatment efficacy.