Cediranib Demonstrates Dual Anticancer Mechanisms: Beyond Anti-Angiogenesis to DNA Repair Suppression

Cediranib is a VEGF receptor inhibitor developed by AstraZeneca. However, researchers at the Yale Cancer Center recently discovered that this investigational anticancer drug has another important function: it can affect the ability of tumor cells to repair DNA damage. When used in combination with PARP inhibitors, it may achieve better anticancer effects. This study was published in the latest issue of Science Translational Medicine.

In a recent Phase 2 clinical trial, cediranib was combined with the PARP inhibitor olaparib to treat patients with recurrent ovarian cancer. The results demonstrated that the combination of cediranib and olaparib not only yielded favorable efficacy in patients harboring BRCA mutations but also improved progression-free survival (PFS) in patients without BRCA mutations.

Olaparib is the first approved PARP inhibitor, an anticancer drug developed based on the principle of “synthetic lethality.” Typically, olaparib is effective only in patients with BRCA gene mutations. These trial results prompted researchers to investigate the reasons why the combination therapy of cediranib and olaparib improves patients’ progression-free survival (PFS).

Initially, they believed that the efficacy of the combination therapy was due to cediranib’s inhibition of angiogenesis. However, further research revealed that, in addition to inhibiting angiogenesis, cediranib can also suppress the expression of BRCA1/2 and RAD51 genes by inhibiting the function of platelet-derived growth factor receptors (PDGFR). These genes play a crucial role in mediating homologous recombination DNA repair. This suggests that cediranib can sensitize tumors to olaparib by inhibiting the homologous recombination DNA repair mechanism.

▲ In mouse tumor models, the combination therapy of cediranib and olaparib significantly reduced tumor size and prolonged survival in mice (Image source: Reference [1])

More encouragingly, in mouse tumor models, cediranib-induced downregulation of gene expression was observed exclusively in tumor cells and not in mouse bone marrow. This enhances the safety profile of the combination therapy with cediranib and olaparib.

“Using cediranib to help inhibit the DNA repair capacity of tumor cells may be effective against various cancers that rely on this signaling pathway,” said Alanna Kaplan, a doctoral student at Yale University and the first author of the study. The researchers’ current goal is to investigate whether this “synthetic lethal” combination therapy can be extended to treat other types of cancer.

References:

[1] Kaplan et al, (2019). Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Science Translational Medicine. DOI: 10.1126/scitranslmed.aav4508

[2] Yale study identifies how cancer drug inhibits DNA repair in cancer cells. Retrieved May 16, 2019, from https://www.eurekalert.org/pub_releases/2019-05/yu-ysi051419.php

▽Follow [WuXi AppTecDe】WeChat Official Account