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THE LANCET Neurology Vol 1 October 2002 http://neurology.thelancet.com334

Newsdesk

Most AMPA-type glutamate receptorsexpressed in human glioblastoma cellslack the GluR2 subunit and aretherefore Ca2+-permeable, accordingto new research. Prevention of Ca2+

influx via these receptors, in responseto endogenous glutamate, inhibitsmigration and proliferation ofglioblastoma cells, and induces theirapoptosis, say Shogo Ishiuchi (GunmaUniversity School of Medicine,Maebashi, Gunma, Japan) andcolleagues. This may provide a newtherapeutic strategy for prevention ofglioblastoma invasion.

Glioblastoma multiforme is themost malignant tumour of the CNS.“In Japan, the 5 year survival rate is6·3%”, says Ishiuchi, “and mediansurvival is 9–12 months, despiteintensive efforts to treat glioblastomawith a combination of surgery,radiation and chemotherapy.” In part,the prognosis is so poor because surgerycan rarely remove all of this extremelyinvasive tumour.

To learn more about glioblastomabiology, Ishiuchi’s team examinedAMPA-receptor expression in 16surgical specimens. AMPA receptorscontain combinations of four subunits,GluR1–4. Receptors that include theadult version of GluR2, which has anarginine at a crucial position within itschannel-lining region, are Ca2+-impermeable; receptors lacking GluR2are permeable to Ca2+.

Most glioblastoma cells from thesurgical specimens expressed GluR1 andGluR4, but few expressed GluR2abundantly. Adenoviral transfer of GluR2into a glioblastoma cell line that expressesonly GluR1 and GluR4 caused the cells tobecome less motile and increased thenumber undergoing apoptosis. In mice,introduction of GluR2 into tumorigenicglioblastoma cells prevented tumourformation in the cerebrum and treatmentwith the AMPA-receptor antagonistYM872 reduced the growth ofsubcutaneously seeded glioblastomas(Nat Med 2002; 8: 971–78).

“This paper shows very nicely thattransfection with GluR2 reduces prolif-eration and migration in glioblastomacells, indicating that calcium is neededfor these behaviours”, says MichaelBennett (Albert Einstein College ofMedicine, NY, USA). Other groupshave also found glutamate receptorantagonists to be antitumour agents, hecomments, “and I would like to knowwhether receptor antagonists workagainst tumour cells injected into thebrain rather than subcutaneously.Nevertheless, even given the potentialfor side-effects associated withreceptor-antagonist treatment, if I hadglioblastoma, I would be glad to try anAMPA antagonist.”

Indeed, the Japanese team iscurrently planning a phase I trial ofAMPA antagonists in the USA. But,warns Ishiuchi, “even if this issuccessful, it will be at least 3–5 yearsbefore this approach to glioblastomatreatment reaches the clinic”.Jane Bradbury

Hopeful channel to glioblastoma treatment revealed

Blocking the activity of the “hedgehog”signalling pathway slows tumourgrowth and may be useful for thetreatment of medulloblastoma—themost common childhood brain cancer.

Despite major advances in therapy,around 40% of patients with medullo-blastoma die from the disease within5 years of diagnosis. “Treatment can behighly aggressive involving many roundsof chemotherapy and infusions ofhaematopoetic stem cells”, says study co-author James Olson (Fred HutchinsonCancer Research Center, WA, USA).

About 20% of patients withmedulloblastoma have a mutation inone of the genes of the hedgehogpathway, which was identified as atreatment target when Phil Beachy andcolleagues (Johns Hopkins University,MD, USA) discovered that it isinhibited by a plant-derived compoundcalled cyclopamine. “Knowing thatsome medulloblastomas were caused bytoo much hedgehog signalling drovethe current experiments withcyclopamine”, recalls Olson.

The team was surprised at thesuccess of the approach: “When webegan this work, we hoped thatcyclopamine would help the 20% ofpatients that had hedgehog mutations”,

explains Olson, “but seven out of sevenpatient samples underwent cell death inresponse to the drug, raising thepossibility that nearly all medullo-blastomas might depend on hedgehogsignalling—even in the absence ofidentifiable gene mutations.” (Science2002; 297: 1559–61)

“This study adds important noveldata”, Guido Reifenberger (Heinrich-

Heine-University, Düsseldorf, Germany)and Torsten Pietsch (University ofBonn, Germany) comment. However,they caution that tumours withaberrant hedgehog signalling, whichalso have other mutations enablingthem to keep growing when thehedgehog pathway is blocked, may beresistant to cyclopamine treatment.Reifenberger and Pietsch suggest that iftumour types that respond favourablyto cyclopamine are identified, “molec-ular analysis of resected tumour-tissuesamples” could be used “to select thosepatients who are most likely tobenefit”.

Olson is hopeful that hedgehogblockers will be in clinical trials within5 years: “We will do everything possibleto move this [research] forward, giventhat these drugs hold promise to behighly effective and minimally toxic.”

“There will undoubtedly be effortsto identify drugs that can be synthesisedin the laboratory, rather than extractedfrom plants”, he adds.Hannah Brown

Hedgehog pathway blockade offers hope for childhood brain cancer

Corn lily: source of cyclopamine

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