Research published in the journal EMBO Molecular Medicine details a novel mechanism that can be used to predict which epithelial ovarian cancer patients (EOC) will be resistant to platinum chemotherapy, the usual treatment for the disease. A significant number of patients with EOC experience resistance to platinum-based chemotherapy, contributing to the disease’s relatively high mortality rate.
The study was co-led by Principal Investigators Assistant Professor Anand Jeyasekharan and Associate Professor David Tan from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS). Jeyasekharan and Tanby identified an association between patients whose cancers showed high levels of the DNA repair protein, RAD51, and the time to relapse after platinum chemotherapy. This association, explain the researchers, offers a target for understanding why certain people are resistant to platinum chemotherapy.
"RAD51 has been identified as a biomarker which can potentially be used to determine the resistance of ovarian cancer to platinum chemotherapy," explained Tan, an oncologist who specializes in gynecological cancers. This is because cancers need RAD51 proteins to repair replication-associated DNA damage - hence the overexpression of the protein could signal the effectiveness of platinum chemotherapy.
To confirm this hypothesis, the researcher utilized automated microscopy and machine learning to determine the levels of RAD51 in individual tumor cells from patient cohorts. They found that cells with higher levels of RAD51 were associated with faster relapse in patients, compared to relapse time for patients with cancer cells with low levels of RAD51. "This study is the first to use machine-learning-based quantitative imaging to measure the expression of this DNA repair protein in tumors" said first author Dr. Michal Hoppe, who is a Research Fellow at CSI Singapore.
This finding paves the path to develop new therapies that augment immune infiltration in cancers and use RAD51 expression as a biomarker to determine the predicted success of individuals. “The lack of immune cell infiltration into the tumors may explain why these high-RAD51 cancers are more resistant to chemotherapy and can be further explored as a biomarker to identify patients who may require novel immunotherapy approaches to improve treatment outcomes," said Tan.
The team says their mechanism is not necessarily limited to ovarian cancer. "Our findings offer a route to refine platinum use in ovarian cancer, but more broadly, this automated microscopy pipeline will be widely applicable to identifying determinants of immune exclusion and chemoresistance in several cancers," concludes Jeyasekharan.