THE accidental 鈥渟witching off鈥� of key genes could be at least as important a
cause of cancer as mutations, many researchers now believe. If they鈥檙e right,
the answer is to turn them back on鈥攁nd trials of drugs that might do this
are already under way.
The traditional view is that cancer is caused by a series of mutations in
tumour suppressor genes. Different mutations are involved in different cancers,
but at some point enough accumulate in one cell to knock out the vital
mechanisms that prevent runaway cell division.
In an increasing number of cancers, however, studies are showing that some
suppressor genes aren鈥檛 damaged, but have simply been switched off by so-called
epigenetic changes鈥攃hanges that don鈥檛 alter the genetic code but can
nevertheless be passed to a cell鈥檚 descendants.
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Such changes involve minor chemical modifications to DNA, or to the histone
proteins around which DNA is wrapped. In cancer, the most important seems to be
methylation, the addition of methyl groups near the start of a gene that turn
the gene off.
While up to 15 tumour suppressor genes may be mutated in a given cancer cell,
there could be many more whose expression is silenced by excessive methylation,
says John Minna of the University of Texas Southwestern Medical Center in
Dallas. 鈥淚t could be a much more important mechanism than DNA sequence mutation
for inactivating tumour suppressor genes,鈥� he says.
Yet because the DNA sequence isn鈥檛 altered, the changes should be relatively
easy to reverse. 鈥淵ou can potentially bring back function,鈥� says Stephen Baylin
of Johns Hopkins University, a pioneer in the field.
Drugs that prevent methylation are already being tested on people.
Decitabine, which inhibits all three enzymes that methylate DNA, is in advanced
trials as a treatment for myelodysplastic syndrome, a type of cancer of white
blood cells.
The drug, made by SuperGen of California, has been around for decades but was
never approved because of concerns about toxicity. The worry with such drugs is
that blocking methylation will not only reactivate tumour suppressor genes in
cancer cells, but will also kill healthy cells by preventing them switching off
genes. But animal tests show that you can block methylation without causing any
obvious harm, says Adrian Bird of Edinburgh University.
This may be because cells take a 鈥渂elt and braces鈥� approach to switching off
big areas of the genome such as women鈥檚 second X chromosome, he says. Blocking
methylation makes little difference because other epigenetic changes, such as
the de-acetylation of histones, keep the genes switched off.
Karl Mettinger, SuperGen鈥檚 chief medical officer, says results from the
latest trials of decitabine are encouraging. The drug is still showing
anti-tumour activity at 10 per cent of the doses used previously, but with
considerably less toxicity. Other methylation inhibitors are also being tested.
Methylgene of Montreal is carrying out trials of an antisense drug called MG98
that blocks production of one of the methylation enzymes.
Such drugs don鈥檛 completely abolish methylation, Bird says, they merely
reduce it. The aim is to tip the balance against the cancer. 鈥淎ll this should be
seen as a battle,鈥� he says. To win the battle, combinations of drugs may be
needed. For example, decitabine is being tried together with phenylbutyrate,
which inhibits histone de-acetylation.
Even if none of these treatments is effective, our growing understanding of
methylation could soon help doctors detect cancers earlier and identify
different types. For example, different cancers should have different
methylation 鈥渟ignatures鈥�. These could reveal if a patient would benefit from a
particular drug. Epigenomics of Berlin is studying samples from patients
enrolled in Methylgene鈥檚 trials, to see if those with a certain methylation
pattern respond better to MG98.
Similar methods could be used to detect cancer earlier. Steven Belinsky of
the Lovelace Respiratory Research Institute in Albuquerque, New Mexico, has
shown that one type of lung cancer could be identified up to three years before
normal diagnosis is possible, by detecting the aberrant methylation of two key
tumour suppressor genes.
Despite all these efforts, those in the field have yet to prove just how
vital a role methylation plays in cancer. 鈥淭here鈥檚 an element of hype,鈥� Bird
cautions. 鈥淪how me a person whose cancer has been cured by preventing
methylation.鈥� Companies such as Methylgene hope they鈥檒l soon be able to do
exactly that.