Lab studies show that combining drugs that target a variety of developmental cell signalling pathways may do a better job of killing deadly brain tumours than single drugs that target one pathway at a time, according to a new study by Johns Hopkins Kimmel Cancer Centre researchers. The combined therapy approach apparently reduces tumour resistance to chemotherapy, they say.
The new research, described in the 15 December 2010 issue of the journal Clinical Cancer Research, found that simultaneously blocking the so-called Notch and Hedgehog pathways, both critical in cell development, did more to decrease growth of human glioblastoma cells and tumour cell clusters compared with drugs aimed at just the Notch pathway. Most standard clinical treatments for glioblastoma currently target just one pathway.
"Our study indicates it may be necessary to simultaneously target multiple development signalling pathways to prevent cancers from becoming resistant to therapy," says Charles Eberhart, M.D., Ph.D., the study's senior author and associate professor of pathology, ophthalmology and oncology. "A single agent is not likely to work for prolonged periods."
Glioblastoma is one of the most aggressive brain tumours, killing nearly every patient within two years. Even when the tumours initially seem to respond to medication, they generally develop resistance. This led researchers to speculate that tumours might compensate for therapy directed against one cancer cell development pathway by turning on a different one.
Eberhart and colleagues studied glioblastoma cell lines to investigate the effects of a gamma-secretase inhibitor, a medication that blocks the Notch receptor, on tumour growth.
They also studied how Notch affects other pathways and evaluated the effects of combined therapy with a Hedgehog inhibitor.
They found that blocking just the Notch pathway in glioblastoma cells using the gamma-secretase inhibitor led to increased activity in both the Hedgehog and Wnt pathways, both important in cell development. Further study showed that certain proteins involved in the Notch pathway interacted directly with proteins in the Hedgehog pathway, suggesting that Notch-targeted therapies can disrupt other cell signalling pathways that fuel tumours.
They next treated a group of glioblastoma cell lines with the gamma-secretase inhibitor, a Hedgehog inhibitor, or both, finding that cell growth decreased slightly with either therapy alone, but by about 90% with dual therapy. The combined treatment also increased natural "programmed" cell death and decreased the ability of cells to form clusters, or colonies. In a group of glioblastoma samples taken during surgical removal of the human cancers, the combination therapy decreased by 50 to 80% the number of colonies formed and decreased the average size of cell clusters.
Clinical trials evaluating inhibitors of Hedgehog or Notch in a number of cancer types are currently under way at Johns Hopkins and several other sites across the country, Eberhart says.
Further studies will examine the relationship among the Notch, Hedgehog and Wnt pathways in glioblastoma and look for other signalling processes that help tumours become resistant to therapy, he says.
The study was supported by the National Institutes of Health, the Brain Tumour Funders Collaborative, the American Cancer Society and a Brain Tumour Spore grant.
Co-authors were Karisa C. Shreck, Luigi Marchionni, Eli E. Bar, and Nicholas Gaiano of Hopkins, and Pete Taylor and Vidya Gopalakrishnan of the University of Texas, M.D. Anderson Cancer Centre in Houston.
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Source: Johns Hopkins Kimmel Cancer Centre
