Discovery

Can a little known drug in AstraZeneca’s pipeline make a comeback as a PARP add-on? Yale scientists explain how

AstraZeneca’s cediranib may not have made the cut as a single agent to treat ovarian cancer, but Yale researchers think it could serve as a powerful add-on to amplify the effects of PARP inhibitors.

Peter Glazer

The theory has been that cediranib works by blocking the formation of new blood vessels, thus depriving tumors of the nutrition and oxygen necessary to live and grow. But in a mouse trial, a team out of Peter Glazer’s lab found that the drug also directly affects pathways involved in DNA repair — a potentially more useful function.

The scientists set out to explain some unexpected results from a recent Phase II study, in which a combination of cediranib with Lynparza (olaparib) improved progression-free survival compared to Lynparza alone (16.5 versus 8.2 months, hazard ratio 0.50; p = 0.007) in patients with relapsed platinum-sensitive ovarian cancer. More importantly, a subset of patients in the trial without documented BRCA1/2 mutations demonstrated superior PFS as well as overall survival. That’s surprising given that a BRCA mutation is often seen as a prerequisite for AstraZeneca and Merck’s star PARP inhibitor to work.

Alanna Kaplan

After exploring the phenomena in mice and cell culture, Glazer and his team — including lead investigator Alanna Kaplan — concluded that cediranib has a direct effect on homology-directed repair, a mechanism that cancer cells can manipulate. The down-regulation, they write in Science Translational Medicine, happens only in tumors but not bone marrow cells, which has traditionally been the dose-limiting factor for PARP drugs.

“Unlike olaparib, it doesn’t directly block a DNA repair molecule, stopping DNA from stitching itself back together. It affects the regulation by which DNA repair genes are expressed,” Glazer added in a statement.

More specifically, cediranib does so through platelet-derived growth factor receptor (PDGFR) inhibition, activation of protein phosphatase 2A (PP2A), and E2F transcription factor 4 (E2F4)/RB transcriptional corepressor like 2 (RB2/p130)–mediated repression of BRCA1/2 and RAD51 gene expression.

The effects are not limited to Lynparza, either; cediranib also sensitized cells to another PARP inhibitor developed by Pfizer, BMN673 (talazoparib).

Back in 2016 AstraZeneca pulled an EMA application for cediranib and axed a monotherapy program for the drug. Its website now lists a Lynparza/cediranib combo as a project in a pivotal phase, with a US filing in ovarian cancer planned for 2020.

The Yale researchers will move on to investigate whether this newfound synthetic lethality — the idea of killing cancer cells more effectively by targeting two genes at the same time — in other cancer types.


Image Source: Shutterstock


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