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The antibacterial Novobiocin inhibits the growth of BRCA-mutated, PARPi-resistant tumors. A study on Mice

An antibiotic developed in the 1950s and completely overtaken by newer medications has been discovered to successfully target and kill cancer cells with a common genetic flaw, according to Dana-Farber Cancer Institute scientists. The antibiotic novobiocin (NVB) selectively destroyed tumor cells with defective BRCA1 or BRCA2 genes, which normally help to repair damaged DNA, according to studies in laboratory cell lines and mice tumor models.

These results were published in Nature Cancer, in a paper titled, “A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors.”

The medicine worked even in tumors that were resistant to PARP inhibitors (PARPi), which have been a popular treatment for tumours that have DNA-repair flaws. The new discoveries have prompted researchers to start a novobiocin clinical trial for patients with malignancies that have significant genetic mutations.

“We're excited to test novobiocin in patients whose tumors have molecular characteristics that indicate a likely response to the drug, both alone and in combination with other agents,” said Alan D'Andrea, MD, director of the Susan F. Smith Center for Women's Cancers and the Center for DNA Damage and Repair at Dana-Farber.

Through a mechanism known as homologous recombination, mutations in the BRCA1 and BRCA2 genes can impair cells' ability to repair DNA (HR). While the scientists write that HR-mediated DNA repair deficit plays a role in the onset and progression of many types of tumors, it also opens up possible therapeutic options. “HR insufficiency also affords new chances for targeted therapy, as seen by BRCA1/2-mutated cancers' high sensitivity to PARPi,” they concluded. However, while tumors may react to PARPi therapy at first, treatment resistance is emerging as a major stumbling block to the clinical usefulness of such medications in patients with HR-deficient malignancies.

The team added, "While numerous causes of PARPi resistance have been revealed, an effective technique for reducing such resistance remains missing."

“PARP inhibitors offer a significant improvement in the treatment of malignancies caused by mutations in BRCA1, BRCA2, or other DNA-repair genes,” D'Andrea added. “They essentially incapacitate tumor cells and induce them to perish by allowing them to amass further genetic damage. For many individuals, they are beneficial, but the cancer eventually becomes resistant and begins to grow again. Drugs that can overcome this resistance are desperately needed.”

BRCA mutations are detected in a significant percentage of breast, ovarian, prostate, and pancreatic cancers, whether hereditary or acquired. The discovery of novobiocin's effectiveness against PARP inhibitor-resistant cancers is the result of two lines of study on a crucial enzyme in tumor cells coming together. D'Andrea and colleagues discovered that cancers with faulty BRCA1 and BRCA2 genes were overly reliant on an enzyme known as POL, or POLQ, for their growth and survival in a 2015 study.

The scientists noted in a new Nature Cancer study that POL has lately emerged as a new attractive therapeutic target for the treatment of HR-deficient malignancies. They wrote, “POL expression is notably high in subtypes of breast and ovarian cancers with HR deficiencies, where it mediates backup DNA double-strand break (DSB) repair, compensating for the loss of HR.” As a result, POL is synthetically deadly with HR, and inhibiting POL causes cell death in HR-deficient malignancies. Depleting POL works in tandem with PARPi to kill HR-deficient cancers, according to research.

The researchers tested thousands of chemicals in BRCA-deficient tumors to determine if any had an effect on tumor growth. Some were new, while others were utilized in authorized medications. The tests were carried out on lab cell lines, organoids (three-dimensional preparations of tumor tissue), and animal models.

Novobiocin stood out among the many compounds and medications evaluated for its capacity to kill tumor cells while leaving normal cells intact. Novobiocin binds directly to the ATPas domain of POL, blocking ATPas activity, and has the same consequences as POL depletion, according to the studies.

Novobiocin inhibited the formation of BRCA1-deficient tumors in mice and also caused cell death in HR-deficient tumor cells generated in the lab, according to studies. In a patient-derived xenograft mouse model (PDX) containing tumors grown from an HR-deficient human high-grade serous ovarian cancer, a combination of novobiocin plus the PARPi olaparib resulted to 100% tumor regression, according to the researchers. While NVB therapy alone resulted in some tumor regression, olaparib monotherapy had little effect on tumor growth inhibition. The researchers speculated that NVB could be used in conjunction with PARPi to improve efficacy and prevent medication resistance in HR-deficient malignancies. “The medication combination caused no significant harm in normal mouse tissue.”

In mice with tumors originating from a patient with germline BRCA1 mutations and acquired PARPi resistance, Novobiocin monotherapy “significantly decreased tumor growth.” Olaparib, on the other hand, was found to be ineffective, demonstrating that novobiocin and PARP inhibition had no cross-resistance. Importantly, the combination of NVB and olaparib suppressed tumor growth much more, with tumor regression occurring within the first two weeks, according to the scientists. “These findings show that NVB can suppress the growth of BRCA1-mutated, PARPi-resistant cancers in vivo, and that NVB plus a PARPi is especially beneficial in treating at least some PARPi-resistant malignancies.”

In vitro research revealed that NVB can overcome numerous PARPi resistance mechanisms, as well as the possibility that higher POL expression levels could be used as a biomarker for novobiocin sensitivity. The scientists concluded that “POL expression levels corresponded with cellular sensitivity to NVB,” implying that “POL expression in a tumor biopsy could provide a handy predictive biomarker for patient participation in future clinical studies with NVB or other POL inhibitors.”

When the researchers delved into the medical literature on novobiocin, they discovered that, despite being produced and used as an antibiotic, it had been tried in a clinical study for patients with difficult-to-treat malignancies in the early 1990s. The medicine had no effect on the majority of the patients, although a tiny percentage of them saw their cancer shrink or stable. “No one knew what the drug's goal was at the time,” D'Andrea says. “Now we have it, and as a result, we know which people are likely to benefit from it.”

According to the authors, depending on the mechanism of resistance, many cancers with acquired PARPi resistance are expected to remain responsive to NVB in clinical settings. In addition to PARP inhibition, “our findings may translate to a possible novel therapeutic for treating HR-deficient tumors,” they concluded. “Most importantly, NVB is an oral, well-tolerated medication that has been studied in Phase I cancer trials previously.”

Dana-Farber researchers will begin a clinical trial of novobiocin for patients with BRCA-deficient malignancies who have developed resistance to PARP inhibitors based on the findings of the study. Novobiocin provides various advantages as a study agent because it is an oral medicine that is safe and licensed for treating another disease, according to D'Andrea. The researchers wrote, "The findings in this trial provide a strong rationale for future clinical studies of NVB alone or in conjunction with PARPi to prevent or overcome PARPi resistance."

“We're excited to test novobiocin in patients whose tumors have molecular markers that indicate a potential response to the treatment, both alone and in combination with other agents,” D'Andrea said.

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