A Chink in Glioblastoma’s Armor

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Science Translational Medicine  23 Apr 2014:
Vol. 6, Issue 233, pp. 233ec71
DOI: 10.1126/scitranslmed.3009252

Glioblastoma (GBM) is a highly lethal brain tumor and, although known to be genetically complex, surprisingly does not share any genetic events across all tumors. Therefore, targeted therapies based on genetic events may not be universally effective. However, because genetic aberrations may cause tumor cells to acquire other properties that are amenable to targeting, Kitambi and colleagues developed a screening approach to identify such weak spots in the GBM armor.

The screening approach used primary patient-derived GBM cells, human fibroblasts, and mouse embryonic stem cells to see whether 1364 drug compounds in the NIH diversity set drug library (http://dtp.nci.nih.gov/index.html) were toxic to GBM. Additional assays were performed on selected compounds from the in vitro screen looking at the impact on development and tumor progression in zebrafish models. Kitambi et al. identified a quinolone alcohol–based compound, which they named Vacquinol-1. Vacquinol-1 potently induced GBM cell death through macropinocytosis, a process characterized by the rapid formation of intracellular vacuoles as a result of engulfment of extracellular fluid. To uncover the mechanism associated with this effect, the authors “silenced” a bunch of intracellular proteins in GBM cells using short hairpin RNA and found that mitogen-activated protein kinase family member MAP2K4 (MKK4) mediated Vacquinol-1-toxicity. Using in vivo zebrafish and mouse xenograft models of human tumors, the authors demonstrated that Vacquinol-1 was effective at attenuating tumor growth through direct injection as well as oral delivery routes.

The authors’ approach uncovered a selective vulnerability of GBM cells to vacuole toxicity and identified Vacquinol-1 as a potential anti-GBM therapy. More broadly, these data suggest that advanced cancers, such as GBM, acquire distinct cellular functions that can be selectively targeted, representing a new paradigm for next-generation cancer therapies.

S. S. Kitambi et al., Vulnerability of glioblastoma cells to catastrophic vacuolization and death induced by a small molecule. Cell 157, 313–328 (2014). [PubMed]

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