AstraZeneca’s experimental cancer drug cediranib was originally developed to inhibit VEGF, a protein that prompts the growth of the blood vessels tumors need to survive. But in clinical trials it hasn’t proven to be all that effective, failing to stack up to Roche’s anti-VEGF blockbuster Avastin.
But now, Yale University researchers have discovered that cediranib has a second function that could improve its prospects for treating cancer. In addition to blocking VEGF, it prevents cancer cells from being able to repair their DNA, causing them to die and promoting tumor shrinkage.
In so doing, cediranib makes tumors more likely to respond to drugs that directly inhibit the DNA repair enzyme PARP, including AstraZeneca’s Lynparza. The Yale team published its findings in the journal Science Translational Medicine.
"There is a lot of interest in the cancer field in developing DNA repair inhibitors because they will greatly help treatments, like radiotherapy and chemotherapy, that aim to destroy DNA in cancer cells," said senior author Peter Glazer, M.D., professor and chair of the department of therapeutic radiology at Yale Cancer Center, in a statement.
Lynparza was initially approved to treat ovarian cancer marked by mutations in BRCA genes. But in a recent phase 2 trial, a combination of the drug with cediranib was effective in non-BRCA-mutated ovarian cancer, leading Glazer and his team on a quest to figure out exactly how the VEGF inhibitor was working.
Stunting the growth of blood vessels to tumors can lead to a depletion of oxygen, which in turn can make it more difficult for cells to repair their DNA. But the Yale researchers discovered in laboratory studies that cediranib actually has a much more direct effect on cancer cells.
It turns out the drug blocks DNA repair by disrupting a process called homology-directed repair. Cediranib breaks up that process by blocking platelet-derived growth factor receptor, which is essential to cell growth. That seems to make cancer cells more sensitive to PARP inhibitors.
AstraZeneca stopped developing cediranib as a monotherapy in 2016 but continued testing it with Lynparza in ovarian cancer and is now predicting an FDA filing for the combo in 2020.
Lynparza, meanwhile, remains an important growth driver for AstraZeneca. The drug’s sales nearly doubled in 2018 to $647 million as it claimed more prescriptions than other PARP inhibitors on the market.
The oncology research community continues to explore the use of PARP inhibitors in other cancers. Last year, a Yale group reported that the drugs may be useful in treating two rare inherited cancers, and U.K. researchers have been exploring Lynparza’s potential in treating glioblastoma
As for the Lynparza-cediranib combo, Glazer is optimistic that the potential of disrupting DNA repair from two different angles will prove to be valuable, and not just in ovarian cancer. "The goal now is to investigate how we can broaden the potential of this synthetic lethality to other cancer types," Glazer said.