Drug Combination Inhibits DNA Repair in Cancer Cells


Researchers seek to investigate how to broaden the potential of cediranib with and olaparib to treat multiple cancer types.

Researchers at Yale Cancer Center have found that a cancer drug cediranib—previously developed to inhibit vascular endothelial growth factor (VEGF) receptors that stimulate the formation of blood vessels—combined with other agents could potentially deliver a lethal blow in cancer by creating DNA repair cells.

"The use of cediranib to help stop cancer cells from repairing damage to their DNA could potentially be useful in a number of cancers that rely on the pathway the drug targets," study lead investigator Alanna Kaplan said in a press release. "If we could identify the cancers that depend on this pathway, we may be able to target a number of tumors."

According to the press release, a previous clinical trial found that cediranib—which been found to offer less of a benefit for its intended purpose than the FDA-approved VEGF pathway inhibitor, Avastin—in combination with olaparib is beneficial for a specific form of ovarian cancer. Olaparib, the first approved DNA repair drug, is known to inhibit the DNA repair enzyme PARP and has shown promise killing cancer cells with defects in DNA repair due to mutations in the repair genes BRCA1 and BRCA2.

However, the combination of cediranib and olaparib was effective in ovarian cancer that did not have BRCA1/BRCA2 mutations, leading to the launch of several clinical trials testing the drug duo in different types of cancers, including prostate and lung cancers.

Researchers thought cediranib worked in that clinical trial by shutting down angiogenesis, the stimulation of blood vessel growth. Blocking angiogenesis leads to low-oxygen conditions inside tumors, sometimes called hypoxia. However, the new study found that although cediranib does help stop the growth of new blood vessels in tumors, it has a second and potentially more powerful function. It switches off DNA repair at an early stage in the repair pathway, according to the study authors.

Cediranib makes tumors more sensitive to the effects of olaparib since it stops cancer cells from repairing their DNA by a mechanism called homology-directed repair. This occurs when a healthy strand of DNA is used as a template to repair the identical, but damaged, DNA strand.

Its direct effect comes from inhibiting the platelet-derived growth factor receptor, involved in cell growth. The drug, therefore, works to inhibit both angiogenesis and the ability of tumors to grow by repairing mishaps in their DNA.

The goal now is to investigate how to broaden the potential of this synthetic lethality to other cancer types.

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