Gastric cancer, otherwise known as stomach cancer, does not
respond well to existing treatments and it is currently the third
leading cause of cancer death in the world (after lung and liver
cancer).
Researchers have discovered that certain drugs, currently used
to treat breast, ovarian and pancreatic cancers, could also be used
to treat certain gastric cancers with a particular pattern of
mutations (genomic molecular fingerprint).
Recent research has shown that a specific genomic molecular
fingerprint, called signature 3, is associated with cells that have
defective DNA repair mechanisms, for example due to faulty BRCA1 or
BRCA2 genes which are linked with breast cancer. Cancer cells
harbouring signature 3 have defects that stop them from efficiently
repairing damage to their DNA. Due to their inability to repair DNA
damage, these cells become vulnerable to platinum drugs and PARP
inhibitor drugs, both of which attack DNA, causing it to break.
Since the DNA damage cannot then be repaired, the cancer cell
dies.
Signature 3 could therefore predict which cancers would be
likely to respond to particular drug therapies. Initially found
only in some breast, ovarian and pancreatic cancers, signature 3
may be present in other human cancers, and researchers in this
latest study aimed to find out which other cancers harboured this
clue to drug vulnerability.
"We analysed the cancer genomes of 10,250 patients, performing a
large-scale computational screen across 36 different types of
tumours, looking for the pattern of Signature 3 in each sample. Not
only did we confirm the presence of signature 3 in a significant
percentage of breast, ovarian, and pancreatic cancers, we also
found this molecular fingerprint in approximately 10 per cent of
stomach cancers," said Ludmil Alexandrov of Los Alamos National
Laboratory in the USA.
"This subset of stomach cancer is likely to have a defective DNA
break-repair mechanism, and could therefore be susceptible to
existing treatments such as platinum drugs or PARP inhibitor
drugs.
In addition to discovering the pattern of signature 3 in gastric
cancer, the study quantified its occurrence in other cancer types.
It showed that 30 per cent of ovarian, 27 per cent of breast and 8
per cent of pancreatic cancers exhibit this molecular fingerprint,
a higher percentage than originally thought. Previous research
using whole genome sequencing data showed that pancreatic cancers
harbouring the signature 3 fingerprint responded very well to
platinum therapy. This suggests that the presence of signature 3
could be used as a biomarker to guide targeted therapy for not just
some gastric cancers, but also for breast, ovarian and pancreatic
cancers.
Previous research has shown the importance of two genes, BRCA1
and BRCA2 to breast and ovarian cancer and currently, clinicians
target platinum therapy or PARP inhibitor drugs towards breast and
ovarian cancer patients who have mutations in their BRCA1 and BRCA2
genes. However, this study shows that these two genes are only part
of the story.
"While all the patients with BRCA1 and BRCA2 mutations show this
signature 3 fingerprint, there are also many patients who have
signature 3 but don't have mutations in BRCA1 and BRCA2. By
focusing exclusively on those two genes, clinicians may be missing
many cancer patients with the genomic signature 3 who could benefit
from PARP inhibitor drugs or platinum therapy," says Suet Yi Leung
from the University of Hong Kong.
"Even just for breast cancer, you could potentially double the
population size that could be treated with this therapy."
PARP inhibitor drugs shut down a specific DNA repair enzyme,
poly ADP ribose polymerase, and because they are more targeted,
they cause far fewer side effects than platinum drugs. Olaparib
(trade name Lynparza) is the latest PARP inhibitor drug to be
licenced for use against ovarian cancer, but using Signature 3 as a
marker, this and future PARP inhibitor drugs could be used to treat
other cancer types such as gastric cancers. This would allow
doctors to treat more patients, more effectively.
So far, this has only been shown in a laboratory setting using
genomics. The next steps would be to clinically test these
therapies to see if patients with cancers that have the signature 3
molecular fingerprint really do respond as hoped to these
treatments. It takes many years of research to launch a new drug as
not only does any new treatment have to be effective, it also has
to be proven to be safe in humans. However, PARP inhibitors are
already available and safety tested, which could speed up the
process of approving their use for other cancers.
"This is an extremely exciting finding which shows the
importance of genomic sequencing for personalised healthcare in the
future," said Michael Stratton, Director of the Wellcome Trust
Sanger Institute.
"In years to come, routine genomic analysis of cancers could
show which have the signature 3 fingerprint and inform and
transform treatment of thousands of patients with these specific
breast, ovarian, pancreatic and gastric cancers."
The paper, A mutational signature in gastric cancer suggests therapeutic
strategies, is published in Nature Communications.