Researchers have broken the code of an enzyme that plays a key role in the growth of most cancers, opening a path that potentially leads to a new class of anti-cancer drugs, according to a study released Sunday.
Other scientists who reviewed the study hailed it as a breakthrough
in fundamental cancer biology, but cautioned that much work remained
before the exploit could be translated into next-generation therapies.
An ideal target for chemo
The enzyme, called telomerase, "is an ideal target for chemotherapy
because it is active in almost all human cancer tumours, but inactive
in most normal cells," said Emmanuel Skordalakes, a professor at the
Wistar Institute in Philadelphia who led the study.
"That means that a drug that deactivates telomerase would likely
work against all cancers, with few side effects."
In humans, telomerase adds short sequences of DNA known as telomeres
to the ends of chromosomes, thus preventing damage and the loss of
genetic information when cells divide.
The enzyme is active mainly in cells that multiply frequently, such
as embryonic stem cells, but is switched off in normal adult cells to
avoid problems caused by runaway cell proliferation.
In cancer cells, however, telomerase is activated, allowing the
disease cells to replicate endlessly and achieve what scientists call
"cellular immortality," the hallmark of all cancers.
A decade-long search for telomerase inhibitors has, up to now, been
hampered by a lack of knowledge of how the enzyme is structured.
First complete view
Skordalakes and colleagues are the first to provide a complete view
of a critically important protein within the telomerase molecule.
It reveals, at an atomic level, how the enzyme replicates the tips
of chromosomes, a process critical to the development of tumours.
The breakdown of this same mechanism is also involved in the ageing
process, which means any new inhibitor drugs might also help boost
Main obstacle overcome
The main obstacle blocking research on the complicated architecture
of telomerase was simply gathering a sufficient quantity of the enzyme.
Neither humans nor yeast - the standard laboratory sources - yielded
Skordalakes screened a wide range of organisms, including protozoa
and insects, before discovering that the red flour beetle produced
copious amounts of telomerase in a stable form.
"This was really the breakthrough," he said. "Once we found that the
gene from this organism expressed the protein in the quantities we
needed, we were able to move quickly."
The researchers used a technique called X-ray crystallography that
analyses the patterns of X-rays beamed at molecule crystals to create a
three-dimensional structure of the enzyme's active region.
Knowing how this region - called the telomerase reverse
transcriptase protein (TERT) - is structured made it possible to
decipher how the enzyme works.
"For the first time, we can see how telomerase assembles at the end
of chromosomes in initiate telomere replication," said Skordalakes.
Several scientists who reviewed the study ahead of publication
hailed its significance.
Only one of many steps
They added, though, that it was only one in a series of essential
steps that led to any novel treatment for cancer.
"There is no doubt that having determined the structure of
telomerase is extremely important in understanding cancer biology, and
will probably help lead us in the development of telomerase
inhibitors," Herbie Newell, head of Translational Research at Cancer
Research UK, told AFP.
"But whether these inhibitors will ultimately represent an effective
class of anti-cancer treatments, it is too early to say."
Jon Wilson, a scientist at The Institute of Cancer Research in
London described the research as a "major breakthrough" in the study of
telomeres in the cancer process.
But he, too, cautioned that the development of drugs to deactivate
the enzyme "in a therapeutic setting, although an exciting prospect,
will require a great deal more research." – (Sapa-AFP)