Current Targeted Therapies May Be Effective in Gastric Cancer

Certain drugs currently used to treat breast, ovarian, and pancreatic cancers could also be used to treat certain gastric cancers with a particular genomic molecular fingerprint (pattern of mutations), according to new research published in Nature Communications (2015; doi:10.1038/ncomms9683).

Gastric cancer does not respond well to existing treatments. It is currently the third leading cause of cancer death in the world, after lung cancer and liver cancer.

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 harboring 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. Researchers in this latest study aimed to find out which other cancers harbored this clue to drug vulnerability.

"We analyzed the cancer genomes of 10 250 patients, performing a large-scale computational screen across 36 different types of tumors, 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% of stomach cancers," said corresponding author Ludmil Alexandrov, PhD, Oppenheimer Fellow in theoretical biology and biophysics at Los Alamos National Laboratory in New Mexico.

"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% of ovarian, 27% of breast, and 8% of pancreatic cancers exhibit this molecular fingerprint, a higher percentage than originally thought.

Previous research using whole genome sequencing data showed that pancreatic cancers harboring 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.

"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 2 genes, clinicians may be missing many cancer patients with the genomic signature 3 who could benefit from PARP inhibitor drugs or platinum therapy," said Suet Yi Leung, MD, chair of Gastrointestinal Cancer Genetics and Genomics at the University of Hong Kong. "Even just for breast cancer, you could potentially double the population size that could be treated with this therapy."

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.
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