Simultaneous Treatment of Multiple Metabolic Pathways Better at Blocking Brain Tumor Growth

Chemotherapy directed at two or more of the embryonic metabolic pathways active in brain tumors was significantly more effective in blocking tumor growth than was inhibition of any single pathway.

Multiple early developmental pathways including Notch, Hedgehog, and Wnt function in malignant brain tumors such as medulloblastoma and glioblastoma (GBM). This fact raises the possibility that tumors might compensate for therapy directed against one pathway by upregulating a different one.

Investigators at Johns Hopkins University (Baltimore, MD, USA) carried out experiments designed to determine whether brain tumors show resistance to therapies against Notch, and whether targeting multiple pathways simultaneously would kill brain tumor cells more effectively than monotherapy. To this end, they worked with clusters of GBM cells growing in culture (neurospheres) and with fresh sample of cancerous tissue obtained from patients.

They reported in the December 15, 2010, issue of the journal Clinical Cancer Research that GBM cells were at least partially resistant to long-term treatment with the gamma-secretase Notch suppressor MRK-003. Blocking the Notch pathway in neurospheres caused increased activity in both the Hedgehog and Wnt pathways. Targeting Notch and Hedgehog simultaneously induced apoptosis, decreased cell growth, and inhibited colony-forming ability more dramatically than monotherapy.

Dual treatment of fresh glioblastoma samples with Notch and Hedgehog inhibitors decreased by 50% to 80% the number of colonies formed in culture and decreased the average size of neurospheres.

"Our study indicates it may be necessary to simultaneously target multiple development signaling pathways to prevent cancers from becoming resistant to therapy,” said senior author Dr. Charles Eberhart, associate professor of pathology, ophthalmology, and oncology at Johns Hopkins University. "A single agent is not likely to work for prolonged periods.”

"Clinical trials evaluating inhibitors of Hedgehog or Notch in a number of cancer types are currently under way at Johns Hopkins University and several other sites across the country, said Dr. Eberhart.” Further studies will examine the relationship among the Notch, Hedgehog, and Wnt pathways in glioblastoma and look for other signaling processes that help tumors become resistant to therapy.”

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