Cediranib was found to confer sensitivity to olaparib through downregulation of the homology-directed DNA repair (HDR) pathway in tumor cells, investigators report.
“The objective of this study was to define the effects of cediranib on the HDR pathway of DNA repair,” wrote Alanna R. Kaplan, MD, of Yale University, New Haven, Conn., and colleagues. The report is in.
The researchers explored the effects of combination cediranib and olaparib therapy at the molecular level using various in vitro and in vivo experiments. Tumor growth studies were conducted in a mouse model with sample sizes selected based on prior experience.
“In vitro experiments were performed in biological triplicate unless otherwise stated,” the researchers wrote. “For in vivo experiments, mice were randomly assigned to treatment groups,” they added.
After analysis, the researchers found that cediranib provides sensitivity to olaparib through suppression of the HDR pathway in malignant cells. The downregulation was explained in part by the inducement of hypoxia, which inhibited gene expression of certain factors in the pathway.
“We noted a decrease in the expression of HDR factors BRCA1, BRCA2, and RAD51 in the cediranib-treated groups compared to controls,” the researchers explained.
In addition, the team reported that cediranib alone exhibits direct effects on the HDR pathway outside of mechanisms related to tumor hypoxia.
“This downregulation was seen in mouse tumor xenografts but not in mouse bone marrow, providing a therapeutic window for combining cediranib and olaparib in cancer therapy,” the team wrote.
The researchers acknowledged that a key limitation of the study was the lack of inquiry into the effects of other mutations on the HDR pathway, which could possibly influence the effects of cediranib in tumor cells.
“These findings identify a pathway by which cediranib can alter the DNA repair capacity of cancer cells that has implications for the design of cancer therapies,” the authors concluded.
The study was supported by grant funding from the National Institutes of Health. One of the researchers reported financial affiliations with Trucode Gene Repair, Cybrexa Therapeutics, and Patrys.
SOURCE: Kaplan AR et al. Sci Transl Med. 2019 May 15. .