PARIS & COPENHAGEN, Denmark—Onxeo S.A., an innovative company specialized in the development of orphan oncology therapeutics, has announced results from a preclinical study demonstrating that the synergistic effect of its lead signal-interfering DNA product candidate AsiDNA in combination with various products in the poly (ADP-ribose) polymerase (or PARP) inhibitor class of drugs is able to bypass the genetic restriction of PARP inhibitors.
The results of the study, which establish potential for rapid clinical translation, were recently published online in the article “Drug Driven Synthetic Lethality: bypassing tumor cell genetics with a combination of Dbait and PARP inhibitors” in Clinical Cancer Research with print issue publication to occur as well in the following weeks.
The study in metastatic melanoma characterized the DNA repair inhibition activity of AsiDNA and olaparib by monitoring DNA repair and DNA damage, and analyzed cell survival to standalone and combined treatments of 21 different tumor cell lines, including 12 breast cancer cell lines and three non-tumor cells.
Olaparib is a PARP inhibitor, blocking the enzyme PARP involved in tumor DNA repair, with efficacy validated in patients with BRCA gene mutation, leading to accumulation of DNA double-strand breaks which cannot be repaired. Olaparib is currently approved for women with BRCA-mutated advanced ovarian cancer.
“Olaparib is an inhibitor of PARP proteins, involved in the repair of single-strand breaks (SSBs). Inhibition of PARP lead to an accumulation of unrepaired SSBs, which are converted to double-strand breaks (DSBs) during the DNA replication (S phase of cell cycle). These DSBs are repaired by the homologous recombination repair pathway during the S phase,” says Onxeo’s Wael Jdey, one of the authors of the article. “However, in tumor cells deficient in this specific repair pathway, the resultant DSBs (very toxic DNA lesions) are not repaired, accumulate and lead ultimately to cell death. In fact, olaparib and other PARP inhibitors are efficient only in tumors deficient in the homologous recombination repair (essentially due to BRCA mutations), a phenomenon called synthetic lethality (between PARP inhibition and homologous recombination deficiency).”
“AsiDNA is a double-strand DNA molecule mimicking DSBs. It acts as an agonist of DNA repair pathways, by hijacking and hyperactivating several DNA repair proteins. It induces a false DNA damage signaling and disturbs the recruitment of repair proteins to DNA damage sites. AsiDNA disturbs and inhibits essential DSBs repair pathways (homologous recombination repair and non-homologous end-joining repair) and SSB repair pathways,” Jdey tells DDNews.
Results showed that olaparib and AsiDNA prevent recruitment of different targeted repair enzymes to damaged sites, and the combination of both drugs increases the accumulation of unrepaired damage, resulting in a synergistic increase of cell death in all tumor cells. Synergistic efficacy of the combination treatment was observed in all tested tumor models regardless of BRCA status, while no increase of DNA damage or lethality was observed in healthy cells, suggesting a good safety and tolerability profile. Analysis also demonstrated different molecular mechanisms underlying the response to AsiDNA and olaparib, suggesting that drug resistance to the combination would be a very rare event.
“The PARP inhibitor olaparib is efficient only in a specific tumor population where the homologous recombination repair pathway is deficient,” Jdey explains. “As AsiDNA disturbs and inhibits the homologous recombination repair, it sensitizes all the tumors to PARP inhibitors, independently of their genetic status or their deficiency in the homologous recombination pathway. We called the synergy between olaparib and AsiDNA ‘drug-driven synthetic lethality,’ a unique mechanism of action and therapy technique in the field of DNA repair inhibition.”
“The combined treatment AsiDNA and olaparib was effective in different tumor types and effective independently of their genetic status: triple negative breast cancer, cervical cancer, head and neck cancer, glioblastoma, skin melanoma, colon cancer and blood cancers. The combined treatment was safe toward non-tumor cells and the healthy tissue.” The study also showed that the combination with AsiDNA is effective using six different PARP inhibitors, with no toxicity in non-tumor cells. “AsiDNA sensitizes tumors to different PARP inhibitors: olaparib, veliparib, rucaparib, iniparib, niraparib, talazoparib and AZD2461,” Jdey continues.
Dr. Graham Dixon, chief scientific officer of Onxeo, commented, “PARP inhibitors show significant benefit in cancer patients, but are mostly limited to tumors with BRCA mutations. AsiDNA breaks the cycle of tumor DNA repair by interfering upstream of the DNA repair process, thereby blocking multiple repair pathways and preventing repair regardless of genetic mutation. Combining AsiDNA with already well-researched and FDA-approved PARP inhibitors like olaparib presents a novel, clinically viable strategy with broad applicability. These preclinical results support Onxeo’s strategic assessment and advancement plan for AsiDNA, and bolster our options for continued clinical development of AsiDNA as a monotherapy and in combination with anti-cancer agents.”