A long-running study from Dana-Farber Cancer Institute, published in Nature Cancer and co-funded by OCRA, has discovered that the antibiotic novobiocin is capable of targeting and killing tumor cells in laboratory cell lines and tumor models with BRCA1 or BRCA2 genetic mutations–and is effective even in tumors that have become resistant to PARP inhibitors.
BRCA1 and BRCA2 gene mutations are found in many patients with ovarian cancer. When functioning correctly, BRCA genes are tumor suppressors, producing a protein that helps repair damaged DNA or destroy cells if damage cannot be repaired. PARP is another DNA repair protein, which can be targeted by a class of drugs called PARP inhibitors, to stop cancer cells from repairing and multiplying. PARP inhibitors are particularly effective against tumors with BRCA mutations, but for some patients, cancer cells eventually become resistant to PARP inhibitors and begin growing again. Says Dr. Alan D’Andrea, co-author of the study, “Drugs capable of overcoming this resistance are urgently needed.”
The breakthrough identifying novobiocin’s effectiveness in PARP inhibitor-resistant tumors came about when two sets of studies done by the Stand Up to Cancer Ovarian Cancer Dream Team, supported in part by funding from OCRA, pointed to POLθ, or POLQ, a key enzyme in tumor cells.
In 2015, Ovarian Cancer Dream Team researchers discovered that tumors with poorly-functioning BRCA1 or BRCA2 genes require POLQ to survive and grow.
In this recent study, researchers screened thousands of molecules and drugs in BRCA mutation tumors to look for effects on tumor growth. Of all molecules tested, novobiocin stood out for its ability to kill tumor cells while leaving normal cells unharmed. The protein that novobiocin targets was POLQ, the same target identified in the team’s previous study.
In digging deeper, researchers discovered that novobiocin, which was first developed in the 1950s, was tested in the 1990s in a clinical trial for patients with hard-to-treat cancers. While most of the study’s participants did not see a benefit, a small percentage did. Back then, researchers could not identify what the drug’s target was, and thus, who could best be helped. This recent discovery connects the dots, and opens up a promising pathway for overcoming PARP inhibitor-resistance for a subset of ovarian cancer patients.
Says Alan D’Andrea, co-author of the study, “We’re looking forward to testing novobiocin, alone and in combination with other agents, in patients whose tumors have molecular characteristics indicating a likely response to the drug.”