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THE LANCET Neurology Vol 3 May 2004 http://neurology.thelancet.com264

Newsdesk

Could aspirin help treat brain cancers?A new molecular mechanism that helpsexplain why brain tumours are soefficient at growing their own bloodsupply could see aspirin added totreatment options for these cancers.

A group of researchers fromHarvard University have identified anew tumour suppressor gene—ING4—that is downregulated in all grades ofhuman glioma. Low levels of the gene’sprotein allow brain tumours to recruitmore blood vessels, and therefore helpto drive cancer development (Nature2004; 428: 328–32).

Igor Garkavtsev, who led the team,explains that the gene was identified bysearching GenBank for sequences thatwere similar to a known tumour-suppressor gene called ING1, which hadpreviously been cloned by the groupusing a novel technique for findingcancer-gene candidates. Once they hadidentified ING4—and confirmed that

like its sister gene, ING1, it wasdownregulated in glioma—the teamstarted to wonder whether it might be anew target for therapy.

A common feature of ING proteinsis that they interact with p53—a keyprotein for suppressing cancer develop-ment—and form a complex thatprevents angiogenesis. However, p53 ismutated in many cancers so changes inthis protein alone are unlikely to explainthe extensive angiogenesis that is char-acteristic of advanced brain cancers.

To find out ING4’s specific role,Garkavtsev and co-workers establishedthat the protien is localised to thenucleus, and found that loss of the genecauses over production of angiogenicgenes that are regulated by the nuclearfactor kappa B (NF-�B).

Garkavtsev believes compoundsthat disrupt NF-�B signalling couldprevent angiogenesis in brain tumour

and therefore stop cancers growing.“One of the old and effective

blockers of NF-�B activity is aspirin”,says Garkavtsev. “Addition of aspirin tothe treatment programme of patientswith brain tumours may lead to betterprognosis.” However, the team are alsoplanning to test other drugs in-vitro.

“It seems that ING4 modulates anangiogenic switch and regulates tumourexpansion”, comments Victor Tse,Chief of Neurosurgery at StanfordUniversity. He notes that compoundssimilar to aspirin, which blocks anenzyme called COX2, have previouslybeen implicated as potential treatmentsfor solid tumours, including glioma.

“It’s a good paper and I hope theywill continue to work on braintumours”, says Tse. But, he cautions,“it’s not clear why ING4 is reduced inbrain tumours”.Hannah Brown

Arimoclomol delays progression in ALS mouse modelArimoclomol, a co-inducer of the heat-shock response, rescues motor neuronsfrom cell death, improves musclefunction, and delays disease progress-ion in a mouse model of ALS,according to researchers at the Instituteof Neurology, London, UK. “Theseeffects appear to be due to an increasein the expression of certain heat-shockproteins [HSPs] within motorneurons”, explains senior author LindaGreensmith (Sobell Department ofMotor Neuroscience and MovementDisorders). “The heat-shock responseis a self-defence mechanism that allcells possess”, she continues. “Motorneurons, however, usually have a veryhigh threshold for activation of thisresponse.” Therefore, increasingexpression of HSPs may help to protectmotor neurons and prevent theirdegeneration.

Greensmith and colleagues studiedtransgenic mice expressing a mutantform of human mutant superoxidedismutase (SOD) 1, in which glycine issubstituted for alanine at position 93(SODG93A). At around 70 days old,SODG93A mice develop signs of motor-

neuron degeneration similar to thoseseen in patients with ALS. Theresearchers began treatment of SODG93A

mice with arimoclomol (10 mg/kgdaily) from day 35 and compared theirprogress with that of untreated SODG93A

mice and normal, wild-type mice.First, Greensmith and colleagues

assessed the number of functionalmotor units in the extensor digitorumlongus muscle of the hindlimb. At120 days, SODG93A mice had about eightmotor units compared with 28 motorunits in wild-type mice. However, inSODG93A mice treated with arimo-clomol, the number of motor units wasalmost doubled. The researchers alsofound that arimoclomol improvedsurvival of motor neurons—inparticular the large motor neurons thatare preferentially lost in ALS—in theventral horn of the lumbar spinal cordby 74% compared with non-treatedmutant mice. These improvements inmotor-neuron survival were acc-ompanied by delayed disease onset andan increase in lifespan of 22% (NatMed 2004; 10: 402–05). Even ifarimoclomal treatment was delayed

until signs of the disease were evident,life span was still increased by 18%.

The researchers then investigatedthe underlying mechanism of arimo-clomal treatment by looking at theexpression of heat-shock transcriptionfactor 1 (Hsf-1) and HSPs. They foundthat arimoclomal activated Hsf-1, andboosted expression of two HSPs—HSP70 and HSP90—in the spinal cord.

“We are very hopeful that thiscompound may be of therapeutic valuefor ALS, as well as other neuro-degenerative disorders in whichupregulating the heat shock responsemay also be neuroprotective”,Greensmith told The Lancet Neurology.

“Induction of HSPs in proportionto the stress would have the advantage of avoiding any toxicsequelae of unnecessary expression”,comments Heather Durham(Montreal Neurological Institute,Quebec, Canada). “However, there isstill some question about themechanism by which arimoclomalinduces expression of HSP70 in motorneurons of the mice”.Rebecca Love