Small Inhibitor May Boost Effectiveness of PARP Inhibitors in Some Ovarian Cancers, Mouse Study Finds

Small Inhibitor May Boost Effectiveness of PARP Inhibitors in Some Ovarian Cancers, Mouse Study Finds

A small inhibitor that prevents cells from making ribosomes — the machinery used to produce proteins — may improve the effectiveness of PARP inhibitors in ovarian cancers with mutations in DNA repair genes, a study in mice found.

This inhibitor is a promising approach for ovarian cancers that are no longer susceptible to platinum-based chemotherapy or PARP inhibitors.

The study with this finding, “CX-5461 activates the DNA damage response anddemonstrates therapeutic efficacy in high-gradeserous ovarian cancer,” was published in Nature Communications.

PARP inhibitors such as Lynparza (olaparib) or Zejula (niraparib), are ovarian cancer treatments that block enzymes needed for adequately correcting DNA errors in cells, preventing cancer cells from repairing their DNA, and ultimately causing their death.

Despite their increasing use in ovarian cancer patients, there are cases of resistance to these treatments, and researchers have been working to find strategies to overcome such resistance.

CX-546 is a small molecule inhibitor that targets the polimerase I enzyme, which is needed to produce ribosomal RNA molecules. This inhibitor has shown promise in some blood cancers and also is in a Phase 1 clinical trial (NCT02719977) of solid tumors.

CX-546 also induces DNA damage and, much like PARP inhibitors, it works particularly well in cancers carrying mutations in DNA repair genes, but the two approaches appear to work via distinct biological mechanisms.

Researchers at Peter MacCallum Cancer Center, John Curtin School of Medical Research, and Walter and Eliza Hall Institute of Medical Research, all in Australia, now examined the exact mechanisms used by this novel small molecule inhibitor, and whether it could be used in combination with approved therapies for ovarian cancer.

Results showed that CX-546 induced cell death across a range of ovarian cancer cell lines, and that cells with higher polimerase I activity were more vulnerable to this small molecule inhibitor. CX-5461 also inhibited polymerase I at doses tenfold lower than those used in the ongoing clinical trial.

Additional research showed that CX-546 was preventing polimerase I from reaching its location in the DNA, which caused the DNA to remain open while waiting for the enzyme. This reorganization made the DNA more vulnerable to errors and also prevented cells from replicating their DNA, causing them to stop dividing and die.

This persistent stress in DNA replication and DNA damage was exacerbated in the presence of mutations in genes involved in a pathway of DNA repair called homologous recombination (HR), and resulting in CX-546 also more effectively killing cells with such mutations.

The team then examined the effects of CX-546 in mice with ovarian cancer. The first model carried  a high-grade serous ovarian cancer (HGSOC) with BRCA2 mutations that had been treated with prior platinum-based chemotherapy.

While CX-546 and the PARP inhibitor Lynparza both were effective at extending the lives of these animals — 53 and 67 days, compared with 22 days without treatment — a combination of both was well-tolerated and led to even greater increases in survival (100 days).

Treatment also stabilized disease and extended survival in HGSOC animal models whose cancer cells had BRCA1 mutations and were resistant to both platinum chemotherapy and to the PARP inhibitors Lynparza and Rubraca (rucaparib).

“We are very excited that this new treatment approach shows efficacy in some ovarian cancers that would not have responded to any other treatment,” Elaine Sanij, PhD, from Peter Mac, said in a university press release.

Results also demonstrated that the presence of BRCA mutations and Myc genetic signatures was associated with better responses to CX-5461 in multiple ovarian cancer samples from patients. These signatures may help predict responses to this treatment in future clinical trials, the researchers believe.

“In this report, we demonstrate that CX-5461 has single agent therapeutic efficacy against HR-deficient HGSOC,” they wrote. “Importantly, we demonstrate that CX-5461 has significant therapeutic efficacy against a cisplatin- and olaparib-resistant HGSOC [animal model].”