1950s antibiotic found to kill tumor cells with DNA repair problem

An antibiotic developed in the 1950s and largely supplanted by new drugs, effectively targets and kills cancer cells with a common genetic defect, according to laboratory research by scientists at the Dana-Farber Cancer Institute. The results prompted investigators to initiate a clinical trial of the drug, novobiocin, for patients whose tumors carry the abnormality.

In a study of the journal Natural cancer, researchers found that in cell lines and laboratory tumor models, novobiocin selectively kills tumor cells with abnormal BRCA1 or BRCA2 genes, which help repair damaged DNA. The drug was effective even in tumors resistant to agents known as PARP inhibitors, which have become a therapy of choice for cancers with DNA repair problems.

“PARP inhibitors represent an important advance in the treatment of cancers with defects in BRCA1, BRCA2 or other genes involved in DNA repair. By allowing tumor cells to accumulate additional genetic damage, they neutralize basically the cells and kill them, ”says Alan D’Andrea, MD, director of the Susan F. Smith Center for Women’s Cancers and the Center for DNA Damage and Repair in Dana-Farber and co-lead author of the study with Raphael Ceccaldi from the Institut Curie in Paris. “They are effective for many patients, but eventually the cancer becomes resistant and starts to grow again. Medicines that can overcome this resistance are urgently needed.” D’Andrea added.

BRCA mutations, whether inherited or acquired, are present in a significant percentage of breast, ovarian, prostate and pancreatic cancers. The discovery of the efficacy of novobiocin in tumors resistant to PARP inhibitors came about when two lines of research converged on a key enzyme in tumor cells.

In a study published in 2015, D’Andrea and colleagues found that tumors with malfunctioning BRCA1 and -2 genes are too dependent for their growth and survival on an enzyme known as POLθ, or POLQ. For the new study, they screened thousands of molecules – some new, others used in approved drugs – in BRCA-deficient tumors to see if any had an effect on tumor growth. The screens were performed in laboratory cell lines, in organoids (three-dimensional cultures of tumor tissue) and in animal models.

Among the multitude of molecules and drugs tested, one stood out for its ability to kill tumor cells while leaving normal cells unscathed – novobiocin. The protein that novobiocin targets in cells was eminently familiar to researchers – POLQ, in particular, a part known as the ATPase domain.

When investigators looked at the medical literature on novobiocin, they found a surprise, D’Andrea said. Although developed and used as an antibiotic, it had been tested in the early 1990s in a clinical trial on patients with cancers that are difficult to treat. While most patients did not benefit from the drug, a small number saw their cancer recede or stabilize.

“At the time, nobody knew who the target of the drugs was,” remarks D’Andrea. “Now we are doing it and therefore we have an indication of the patients who might be helped by this.”

Based on the study results, Dana-Farber researchers will launch a clinical trial of novobiocin for patients with BRCA-deficient cancers who have acquired resistance to PARP inhibitors. Because it is an oral drug that is safe and approved for the treatment of another disease, novobiocin offers several advantages as a study agent, comments D’Andrea.

“We look forward to testing novobiocin, alone or in combination with other agents, in patients whose tumors have molecular features indicating a likely response to the drug,” D’Andrea said.

Republished courtesy of the Dana Farber Cancer Institute.

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