For a second time, researchers will test an antibiotic discovered in the 1950s as a potential treatment for cancer. 

The first attempt to study the drug, novobiocin, in patients with cancer was a small clinical trial conducted 30 years ago. A young woman with advanced breast cancer responded to the drug and survived for 2 years, but most of the other participants in the trial did not benefit. 

Three decades later, researchers at the Dana-Farber Cancer Institute have “rediscovered” novobiocin. They found it while testing thousands of compounds against cancer cells that had become resistant to drugs known as PARP inhibitors. These drugs are used to treat patients with various cancers, including ovarian, breast, and prostate cancers.

“Lo and behold, novobiocin was one of the very top hits in our drug screen,” said Alan D’Andrea, M.D., who directs the Center for DNA Damage and Repair at Dana-Farber. Although novobiocin is no longer used to treat bacterial infections in people, the drug is still produced for veterinary medicine and remains in drug libraries for research. 

Novobiocin blocks the activity of a protein called DNA polymerase theta (Polθ or POLQ), which helps repair DNA that has become damaged as cells grow and divide. Cancer cells that cannot repair their damaged DNA die. 

Polθ and the protein targeted by PARP inhibitors are both involved in a “backup” form of DNA repair. These backup pathways become particularly important when a repair process known as homologous recombination stops working, as happens in some cells with mutations in the BRCA1 or BRCA2 genes.

In a new study, Dr. D’Andrea and his colleagues found that novobiocin killed cancer cells with deficiencies in homologous recombination repair. The drug also shrank tumors in mouse models of triple-negative breast cancer that had mutations in DNA-repair genes. The researchers reported their findings in Nature Cancer on June 17.  
 
“Most important, we found that novobiocin killed tumors that had become resistant to a PARP inhibitor,” said Dr. D’Andrea. “Novobiocin was even more effective in combination with a PARP inhibitor.” 

Based on these results, his team is developing NCI-supported clinical trials to test the drug’s ability to treat cancers that have become resistant to PARP inhibitors.

The Dana-Farber team is not alone in finding that a Polθ inhibitor may have anticancer activity. Scientists from the Institute for Cancer Research in London and their colleagues have reported that a Polθ inhibitor called ART558 also can kill cancer cells and tumors that have become resistant to PARP inhibitors. 

Using a Polθ inhibitor in combination with a PARP inhibitor in patients with cancers that have mutations in BRCA genes might prevent resistance from emerging in the first place, the latter group of researchers reported in Nature Communications on June 17.

PARP inhibitors, including olaparib (Lynparza) and talazoparib (Talzenna), block an enzyme called poly (ADP-ribose) polymerase, or PARP, that helps repair damaged DNA. The drugs are used to treat cancers that have alterations in DNA-repair genes, namely BRCA1 or BRCA2. 

Cells that have BRCA mutations are forced to rely on an alternative DNA repair process that involves PARP. As a result, these cells are particularly sensitive to PARP inhibitors and die. This is known as synthetic lethality.

However, cancers eventually find ways to bypass the loss of PARP. “Nearly all women with ovarian cancer who are treated with PARP inhibitors will experience a relapse,” said Dr. D’Andrea. “When the tumor grows back, it is resistant to PARP inhibitors, and at this point there are no treatments—it’s a terrible clinical problem.” 

For more details go through: Archives in Cancer Research.

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Archives in Cancer Research