Researchers identify an attractive target for a deadly form of ovarian cancer


Epithelial ovarian cancer (EOC), the most common type of ovarian cancer, is extremely hard to treat because of its high tumor heterogeneity. More than 70% of the patients respond to initial treatment, but most of them will develop resistance and relapse. Despite the emergence of various new drugs, the poor prognosis of EOC has not improved for many years.

A team of researchers from the US and Japan recently have identified an attractive target for developing EOC drugs. The team is composed of researchers from Houston Methodist Research Institute, University of Texas MD Anderson Cancer Center, Osaka University Graduate School of Medicine, and Niigata University Graduate School of Medical and Dental Sciences.

Michiko Kodama, first author of the study, and colleagues set out to search new drug targets for EOC. They performed two screens, one based on a pooled shRNA library and the other based on a genome-wide CRISPR/Cas9 library. The screens revealed a number of potential drug targets. One of them, KPNB1, attracted the most interest.

The KPNB1 gene encodes a protein known as importin subunit beta-1, which is known to function in nuclear protein import. In this work, the researchers discovered that KPNB1 overexpression promoted EOC cell proliferation whereas KPNB1 inhibition induced apoptosis, indicating that KPNB1 acts as an oncogene in EOC. Further research showed that KPNB1 regulates many proteins associated with the cell cycle. Consistently, EOC patients who had elevated KPNB1 levels tended to have earlier recurrence and worse prognosis.

Ivermectin is a broad-spectrum antiparasitic agent that is widely used to treat parasites. This study showed that it has antitumor effects and it acts on KPNB1. In vitro and in vivo experiments demonstrated that combining ivermectin with paclitaxel (a drug approved for many cancers including EOC) is more efficacious compared to using the drugs individually.

Taken together, the study identifies KPNB1 as a druggable target for EOC and highlights the antitumor effect of ivermectin on EOC. Since ivermectin is being used for human parasitic diseases, repurposing it to treat EOC is much more time-saving and cost-effective than developing a novel drug.

Kodama and colleagues have detailed their findings in a new paper titled "In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer," appearing in the journal PNAS.
 
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