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Hopeful channel to glioblastoma treatment revealed
Newsdesk Hedgehog pathway blockade offers hope for childhood brain cancer The team was surprised at the success of the approach: “When we began this work, we hoped that cyclopamine would help the 20% of patients that had hedgehog mutations”,
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Photograph used by permission of USDA-ARS Poisonous Plant Research Lab
Blocking the activity of the “hedgehog” signalling pathway slows tumour growth and may be useful for the treatment of medulloblastoma—the most common childhood brain cancer. Despite major advances in therapy, around 40% of patients with medulloblastoma die from the disease within 5 years of diagnosis. “Treatment can be highly aggressive involving many rounds of chemotherapy and infusions of haematopoetic stem cells”, says study coauthor James Olson (Fred Hutchinson Cancer Research Center, WA, USA). About 20% of patients with medulloblastoma have a mutation in one of the genes of the hedgehog pathway, which was identified as a treatment target when Phil Beachy and colleagues (Johns Hopkins University, MD, USA) discovered that it is inhibited by a plant-derived compound called cyclopamine. “Knowing that some medulloblastomas were caused by too much hedgehog signalling drove the current experiments with cyclopamine”, recalls Olson.
Corn lily: source of cyclopamine
explains Olson, “but seven out of seven patient samples underwent cell death in response to the drug, raising the possibility that nearly all medulloblastomas might depend on hedgehog signalling—even in the absence of identifiable gene mutations.” (Science 2002; 297: 1559–61) “This study adds important novel data”, Guido Reifenberger (Heinrich-
Heine-University, Düsseldorf, Germany) and Torsten Pietsch (University of Bonn, Germany) comment. However, they caution that tumours with aberrant hedgehog signalling, which also have other mutations enabling them to keep growing when the hedgehog pathway is blocked, may be resistant to cyclopamine treatment. Reifenberger and Pietsch suggest that if tumour types that respond favourably to cyclopamine are identified, “molecular analysis of resected tumour-tissue samples” could be used “to select those patients who are most likely to benefit”. Olson is hopeful that hedgehog blockers will be in clinical trials within 5 years: “We will do everything possible to move this [research] forward, given that these drugs hold promise to be highly effective and minimally toxic.” “There will undoubtedly be efforts to identify drugs that can be synthesised in the laboratory, rather than extracted from plants”, he adds. Hannah Brown
Hopeful channel to glioblastoma treatment revealed Most AMPA-type glutamate receptors expressed in human glioblastoma cells lack the GluR2 subunit and are therefore Ca2+-permeable, according to new research. Prevention of Ca2+ influx via these receptors, in response to endogenous glutamate, inhibits migration and proliferation of glioblastoma cells, and induces their apoptosis, say Shogo Ishiuchi (Gunma University School of Medicine, Maebashi, Gunma, Japan) and colleagues. This may provide a new therapeutic strategy for prevention of glioblastoma invasion. Glioblastoma multiforme is the most malignant tumour of the CNS. “In Japan, the 5 year survival rate is 6·3%”, says Ishiuchi, “and median survival is 9–12 months, despite intensive efforts to treat glioblastoma with a combination of surgery, radiation and chemotherapy.” In part, the prognosis is so poor because surgery can rarely remove all of this extremely invasive tumour.
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To learn more about glioblastoma biology, Ishiuchi’s team examined AMPA-receptor expression in 16 surgical specimens. AMPA receptors contain combinations of four subunits, GluR1–4. Receptors that include the adult version of GluR2, which has an arginine at a crucial position within its channel-lining region, are Ca2+impermeable; receptors lacking GluR2 are permeable to Ca2+. Most glioblastoma cells from the surgical specimens expressed GluR1 and GluR4, but few expressed GluR2 abundantly. Adenoviral transfer of GluR2 into a glioblastoma cell line that expresses only GluR1 and GluR4 caused the cells to become less motile and increased the number undergoing apoptosis. In mice, introduction of GluR2 into tumorigenic glioblastoma cells prevented tumour formation in the cerebrum and treatment with the AMPA-receptor antagonist YM872 reduced the growth of subcutaneously seeded glioblastomas (Nat Med 2002; 8: 971–78).
“This paper shows very nicely that transfection with GluR2 reduces proliferation and migration in glioblastoma cells, indicating that calcium is needed for these behaviours”, says Michael Bennett (Albert Einstein College of Medicine, NY, USA). Other groups have also found glutamate receptor antagonists to be antitumour agents, he comments, “and I would like to know whether receptor antagonists work against tumour cells injected into the brain rather than subcutaneously. Nevertheless, even given the potential for side-effects associated with receptor-antagonist treatment, if I had glioblastoma, I would be glad to try an AMPA antagonist.” Indeed, the Japanese team is currently planning a phase I trial of AMPA antagonists in the USA. But, warns Ishiuchi, “even if this is successful, it will be at least 3–5 years before this approach to glioblastoma treatment reaches the clinic”. Jane Bradbury
THE LANCET Neurology Vol 1 October 2002
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Photograph used by permission of USDA-ARS Poisonous Plant Research Lab
Blocking the activity of the “hedgehog” signalling pathway slows tumour growth and may be useful for the treatment of medulloblastoma—the most common childhood brain cancer. Despite major advances in therapy, around 40% of patients with medulloblastoma die from the disease within 5 years of diagnosis. “Treatment can be highly aggressive involving many rounds of chemotherapy and infusions of haematopoetic stem cells”, says study coauthor James Olson (Fred Hutchinson Cancer Research Center, WA, USA). About 20% of patients with medulloblastoma have a mutation in one of the genes of the hedgehog pathway, which was identified as a treatment target when Phil Beachy and colleagues (Johns Hopkins University, MD, USA) discovered that it is inhibited by a plant-derived compound called cyclopamine. “Knowing that some medulloblastomas were caused by too much hedgehog signalling drove the current experiments with cyclopamine”, recalls Olson.
Corn lily: source of cyclopamine
explains Olson, “but seven out of seven patient samples underwent cell death in response to the drug, raising the possibility that nearly all medulloblastomas might depend on hedgehog signalling—even in the absence of identifiable gene mutations.” (Science 2002; 297: 1559–61) “This study adds important novel data”, Guido Reifenberger (Heinrich-
Heine-University, Düsseldorf, Germany) and Torsten Pietsch (University of Bonn, Germany) comment. However, they caution that tumours with aberrant hedgehog signalling, which also have other mutations enabling them to keep growing when the hedgehog pathway is blocked, may be resistant to cyclopamine treatment. Reifenberger and Pietsch suggest that if tumour types that respond favourably to cyclopamine are identified, “molecular analysis of resected tumour-tissue samples” could be used “to select those patients who are most likely to benefit”. Olson is hopeful that hedgehog blockers will be in clinical trials within 5 years: “We will do everything possible to move this [research] forward, given that these drugs hold promise to be highly effective and minimally toxic.” “There will undoubtedly be efforts to identify drugs that can be synthesised in the laboratory, rather than extracted from plants”, he adds. Hannah Brown
Hopeful channel to glioblastoma treatment revealed Most AMPA-type glutamate receptors expressed in human glioblastoma cells lack the GluR2 subunit and are therefore Ca2+-permeable, according to new research. Prevention of Ca2+ influx via these receptors, in response to endogenous glutamate, inhibits migration and proliferation of glioblastoma cells, and induces their apoptosis, say Shogo Ishiuchi (Gunma University School of Medicine, Maebashi, Gunma, Japan) and colleagues. This may provide a new therapeutic strategy for prevention of glioblastoma invasion. Glioblastoma multiforme is the most malignant tumour of the CNS. “In Japan, the 5 year survival rate is 6·3%”, says Ishiuchi, “and median survival is 9–12 months, despite intensive efforts to treat glioblastoma with a combination of surgery, radiation and chemotherapy.” In part, the prognosis is so poor because surgery can rarely remove all of this extremely invasive tumour.
334
To learn more about glioblastoma biology, Ishiuchi’s team examined AMPA-receptor expression in 16 surgical specimens. AMPA receptors contain combinations of four subunits, GluR1–4. Receptors that include the adult version of GluR2, which has an arginine at a crucial position within its channel-lining region, are Ca2+impermeable; receptors lacking GluR2 are permeable to Ca2+. Most glioblastoma cells from the surgical specimens expressed GluR1 and GluR4, but few expressed GluR2 abundantly. Adenoviral transfer of GluR2 into a glioblastoma cell line that expresses only GluR1 and GluR4 caused the cells to become less motile and increased the number undergoing apoptosis. In mice, introduction of GluR2 into tumorigenic glioblastoma cells prevented tumour formation in the cerebrum and treatment with the AMPA-receptor antagonist YM872 reduced the growth of subcutaneously seeded glioblastomas (Nat Med 2002; 8: 971–78).
“This paper shows very nicely that transfection with GluR2 reduces proliferation and migration in glioblastoma cells, indicating that calcium is needed for these behaviours”, says Michael Bennett (Albert Einstein College of Medicine, NY, USA). Other groups have also found glutamate receptor antagonists to be antitumour agents, he comments, “and I would like to know whether receptor antagonists work against tumour cells injected into the brain rather than subcutaneously. Nevertheless, even given the potential for side-effects associated with receptor-antagonist treatment, if I had glioblastoma, I would be glad to try an AMPA antagonist.” Indeed, the Japanese team is currently planning a phase I trial of AMPA antagonists in the USA. But, warns Ishiuchi, “even if this is successful, it will be at least 3–5 years before this approach to glioblastoma treatment reaches the clinic”. Jane Bradbury
THE LANCET Neurology Vol 1 October 2002
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.