“Aggressive pancreatic tumours may be treatable with a new class of drugs,” BBC News has reported today.
Pancreatic cancer is one of the most aggressive forms of cancer, and
very few patients diagnosed with the disease survive beyond five years
after diagnosis, while most die within a year. However, relatively
little is known about what the causes of the disease are.
This news highlights a new study in which researchers set out to
explore new potential genetic causes of pancreatic cancer. The research
involved a combination of mouse and human cell studies that looked at
genes that may be involved, with results suggesting that a gene called
USP9X can greatly raise the risk when not functioning normally. The role
of the gene is to stop cells dividing uncontrollably, but tests in mice
showed it was blocked from working in about 50% of pancreatic tumour
cells in mice. The USP9X gene itself was not faulty, but proteins and
other chemicals had interacted with the gene to switch it off in the
tumour cells. Looking at the gene in human cancer patients showed the
gene tended to be less active in tumour cells than in normal cells.
This research may be useful but, despite media claims that existing
drugs may be able to remove chemicals interacting with USP9X, this study
did not test a new class of drug, or indeed any drug, to see if it was
effective at treating or preventing pancreatic cancer in humans.
Consequently, media reports that there is a “new drug hope” for
pancreatic cancer are a little premature, although the research
certainly highlights some areas for future research to explore.
Where did the story come from?
The study was carried out by a large collaboration of international
researchers from Europe, Australia and the USA. It was funded by Cancer
Research UK.
The study was published in the
peer-reviewed scientific journal Nature.
The media reporting of this study was generally balanced. However,
some reports that existing drugs “could be an effective way of treating
pancreatic cancer” are not proven by this laboratory study, which
explored the mechanisms that may be behind pancreatic cancer rather than
testing any drugs in patients with the condition.
What kind of research was this?
Pancreatic cancer is one of the most aggressive and hard-to-treat
forms of cancer, and patients diagnosed with the condition generally
have a low rate of long-term survival. The causes of pancreatic cancer
are relatively unknown, so in recent years there has been a great deal
of research in this area.
This latest research was a laboratory study investigating the role
different genes might have in the cause and progression of pancreatic
cancer. It involved experiments in both mice bred to have pancreatic
cancer and extracted human pancreatic cancer cells. It also looked at
the genetics of the cells of pancreatic cancer patients, although it did
not perform any direct experiments in living humans.
Within human DNA there are sections of code that perform a specific
function, and these are known as genes. These genes contain instructions
for making proteins, which then go on to perform a host of important
functions in the body. Mutations within genes can either stop the body
making key proteins, or cause the body to make abnormal versions of
proteins so that they do not work in a typical way. The authors said
that previous research established that pancreatic cancer is associated
with common mutations in genes called KRAS, CDKN2A, TP53 and SMAD4.
The authors said that, out of all these mutations, KRAS was most
commonly associated with pancreatic cancer, and therefore researchers
sought to investigate what other genes worked with KRAS to cause or
accelerate pancreatic cancer. The normal function of the KRAS gene is to
produce a protein involved in regulating cellular division, as occurs
when cells reproduce themselves.
What did the research involve?
Mice were bred with genetic mutations in a gene called KRAS within
their pancreas cells, which meant they would be highly likely to develop
cancer of the pancreas during their lives. The scientists then
engineered a selection of 20 further candidate genes to be mutated in
each mouse's pancreas to see how they influenced cancer development in
their pancreatic cells. The basic premise is that there might be some
interaction between these mutant genes and KRAS that would encourage the
development of pancreatic cancer.
After testing whether these various mutations increased the risk of
cancer developing in the pancreatic cells of living mice, the
researchers further tested those genes that appeared to have the
greatest influence, to understand better how they worked. To determine
whether the most important candidate genes in mice were also important
in human cancer, the scientists used human pancreatic cells taken from
patients during surgery to remove their cancer. The cancer cell DNA of
100 people was isolated and tested to see if it had errors in any of the
candidate genes previously highlighted in the mice.
The activity of candidate genes was also tested in a second cohort of
42 patients with pancreatic cancer to see if the gene was being “read”
correctly by the cellular machinery to produce proteins in a normal way.
The protein levels of a further 404 patients with pancreatic cancer
were analysed to see what proteins were elevated or reduced in these
cells, and how these levels might relate to the genetics of the cells.
The protein levels of the cancerous cells were compared with normal
cells to highlight differences.
The researchers then performed a statistical analysis of their study results, which was done in an appropriate manner.
What were the basic results?
The key findings of the study were as follows:
- The most commonly mutated gene out of the 20 in the mice model
of pancreatic cancer tested was called USP9X. This was mutated (and
therefore inactive) in over 50% of the mouse tumours tested.
- In the mice cells that were engineered to have no USP9X gene there was a faster progression of pancreatic cancer.
- In human cells, the researchers found that in the majority of
cases (88 out of 100) the genetic code of the USP9X gene was normal,
therefore the problems were likely to be in the regulation of the gene –
how fast or slow the cell machinery reads the genetic code to produce
proteins from it.
- In these cases, low expression of USP9X and low protein levels
from the gene correlated with worse survival after surgery for
pancreatic cancer.
- In the second cohort of 42 patients with pancreatic cancer, low
expression of USP9X correlated with cancer that was “metastatic”, which
meant it had spread to other parts of the body. Generally, metastatic
cancers are harder to treat and pose greater danger to patients.
- In a subset of 404 patients with pancreatic cancer, the level of
protein produced when the USP9X is read by the cellular machinery was
lower than in normal pancreatic cells.
How did the researchers interpret the results?
The researchers concluded that “USP9X is a major tumour suppressor
gene” that has not previously been implicated in pancreatic cancer. A
tumour suppressor gene means that, when functioning correctly, the gene
stops the cell becoming cancerous, but if the gene or its regulation
goes wrong, it can lead to cancer. The authors also concluded that the
USP9X gene is inactivated in cancer cells not because it has mutations
(mistakes in its genetic code) but rather because chemicals have
attached to the surface of the gene to turn it down or off. These
attached substances, known as “tags”, prevent it from producing proteins
in a normal way.
Conclusion
This laboratory study has examined various genetic factors in mice,
extracted cells and living patients to show that the USP9X gene may have
a role in some people with pancreatic cancer. In human pancreatic
cancer cells, the USP9X gene was found to produce lower levels of a
cancer-suppressing protein than in normal pancreatic cells. Furthermore,
the mice model showed that reducing the function of the USP9X gene
accelerated the progression of cancer. Taken together, this suggests
that USP9X has an important role in a subset of pancreatic cancers that
have problems in the regulation of this gene.
This study is at an early stage and would need to be confirmed in
more people to see how common this mutation is in people with pancreatic
cancer, and whether the regulation of this gene is similar in most
patients. Cancer is a complex disease and typically involves numerous
genetic mutations and problems with genetic regulation. Therefore, even
if a method or drug was available to ensure USP9X functions normally,
other genes may also have a role in pancreatic cancer. Furthermore,
there is likely to be a range of environmental factors that also
influence a person’s risk of developing pancreatic cancer to some
extent.
In the various media reports, clinical experts are quoted as having
said that some existing cancer drugs that work to strip away genetic
tags “are showing promise in lung cancer”. Hence, some commentators have
suggested that these drugs may work in people with USP9X inactivity
caused by genetic tags.
This research may be useful but it is important to note that this
study did not test a new class of drugs to see if it was effective at
treating or preventing pancreatic cancer. Consequently, media reports
that there is a “new drug hope” for pancreatic cancer are a little
premature. For example, USP9X may not be the only factor that increases
an individual’s risk of cancer, so even if a drug could successfully
reverse tagging of the gene it would not guarantee that they would have
no risk of the disease.
However, this study does highlight a gene that was not previously
thought to be important in pancreatic cancer, and this will be a useful
focus for future research to understand better the biology of pancreatic
cancer.
Analysis by
Bazian
