Research ArticleBRAIN TUMORS

KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice

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Science Translational Medicine  15 Aug 2018:
Vol. 10, Issue 454, eaar2718
DOI: 10.1126/scitranslmed.aar2718

A serendipitous metabolic target for glioblastoma

Glioblastoma (GBM), one of the most aggressive brain cancers, is associated with poor prognosis and low survival rate. GBM stem cells contribute to aggressive GBM growth. Polson et al. hypothesized that promoting neural differentiation could have therapeutic effects. While testing the therapeutic properties of the small-molecule KHS101, previously shown to promote neural differentiation, the authors made the serendipitous discovery that KHS101 exerted cytotoxic activity in multiple patient-derived GBM cell lines by disrupting cell metabolism and promoting autophagy. In vivo administration of KHS101 reduced tumor growth and prolonged survival in patient-derived xenograft mouse models of GBM. The authors suggest that targeting cell metabolism using small molecules might be effective for treating GBM.


Pharmacological inhibition of uncontrolled cell growth with small-molecule inhibitors is a potential strategy for treating glioblastoma multiforme (GBM), the most malignant primary brain cancer. We showed that the synthetic small-molecule KHS101 promoted tumor cell death in diverse GBM cell models, independent of their tumor subtype, and without affecting the viability of noncancerous brain cell lines. KHS101 exerted cytotoxic effects by disrupting the mitochondrial chaperone heat shock protein family D member 1 (HSPD1). In GBM cells, KHS101 promoted aggregation of proteins regulating mitochondrial integrity and energy metabolism. Mitochondrial bioenergetic capacity and glycolytic activity were selectively impaired in KHS101-treated GBM cells. In two intracranial patient-derived xenograft tumor models in mice, systemic administration of KHS101 reduced tumor growth and increased survival without discernible side effects. These findings suggest that targeting of HSPD1-dependent metabolic pathways might be an effective strategy for treating GBM.

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