The researches find that interest in the cancer field in developing DNA repair inhibitors because they greatly help treatments, therefore like radiotherapy and chemotherapy; Because that aim to destroy DNA in cancer cells;” said the senior author of the study at Yale Cancer Center, Peter M. Glazer, M.D., chair of the Department of Therapeutic Radiology; the Robert E. Hunter Professor of Therapeutic Radiology; and professor of genetics.
Interest in the cancer field
DNA repair occurs in several different ways; therefore which is why inhibitors of these specific techniques could be so valuable; Glazer said. Because “People are recognizing that manipulating DNA repair could be very advantageous to boosting the benefit of traditional cancer treatment.”
“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;” said the study’s lead investigator, Alanna Kaplan, a member of Glazer’s team. “If we could identify the cancers that depend on this pathway; we may be able to target a number of tumors.”
However, a recent clinical trial find the combination of cediranib and olaparib (registered as Lynparza) is beneficial in a specific form of ovarian cancer. Olaparib, the first approve DNA repair drug, is know to inhibit a DNA repair enzyme call PARP and has show promise killing cancer cells with defects in DNA repair due to mutations in the DNA repair genes BRCA1 and BRCA2.
Several clinical trials testing
But the combination of cediranib and olaparib is 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 cancer. Glazer and his team wanted to understand how cediranib exerted such a powerful effect.
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. Two decades ago, Glazer demonstrated that, among other things, low oxygen seemed to negatively affect DNA repair. In short, the researchers believed hypoxia caused by cediranib led to weak DNA repair.
More sensitive to the effects
Cediranib makes tumors more sensitive to the effects of olaparib because it stops cancer cells from repairing their DNA by a mechanism called homology-directed repair (HDR). This occurs when a healthy strand of DNA is used as a template to repair the identical, but damaged, DNA strand, he added.
Cediranib’s direct effect comes from inhibiting the platelet-derived growth factor receptor (PDGFR), which is 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 capacity of the drug to harm blood vessel formation was not a surprise. But its direct effect on DNA repair through the PDGF receptor is completely unexpect,” Glazer said.