New way to predict who will respond to cancer therapies that block Wnt production

Scientists from Duke-NUS Medical School, Erasmus University Medical Center, Yale-NUS College, and Duke University have identified possible means to prognosticate who will respond to cancer therapies that inhibit Wnt production.

This finding leads the objective of personalized medicine in cancer therapy a step nearer to reality.

Wnt proteins are vital signaling molecules that enable neighboring cells to communicate with each other. But over-production of this protein causes cancers. Wnt is a key driver of several common cancers, such as breast and colorectal cancers and also pancreatic and leukemia cancer. Several mutations can stimulate an excess activity of Wnt, and it has been difficult to identify reliable biomarkers.

This study, published in the Cancer Research journal, has found an actionable biomarker—a protein known as RNF43—that is modified in a unique class of Wnt-addicted cancers.

RNF43 is one instance that can help us predict whether a cancer cell might be dependent on the Wnt pathway.”

Babita Madan, Study Corresponding Author and Assistant Professor, Duke-National University of Singapore Medical School

Madan is a researcher in Duke-NUS Cancer and Stem Cell Biology program.

RNF43 is often mutated in endometrial, mucinous ovarian, colorectal, pancreatic, and gastric cancers.

The drug, which was developed together by Duke-NUS and the Agency for Science, Technology, and Research, is an innovative tiny molecule drug candidate that targets various cancers such as ovarian, colorectal, and pancreatic cancers. At present, it is in Phase 1B human trials. It was utilized in this pre-clinical study to identify whether cancers presenting RNF43 mutations would respond to Wnt inhibitor therapy.

It has been shown in the past that RNF43 regulates cell surface Wnt receptors and RNF43 mutations could cause sensitivity to Wnt inhibitor in pancreatic cancers.”

Yu Jia, Study First Author and Research Fellow, Duke-National University of Singapore Medical School

This study widens the landscape of actionable RNF43 mutations, paving the way for additional patients to gain from these therapies. As a next step, the team believes that the study could be useful to clinicians who are involved in clinical trials for Wnt inhibitors to create a look-up table on the basis of their list of actionable RNF43 mutations.

This is another major step towards bringing personalised medicine to cancer patients in Singapore and across the globe. Being able to customise treatments to the unique genetic signature of a patient's cancer will allow healthcare providers to better customise treatment plans and greatly increase the chance of real impact on the disease.”

Patrick Casey, Professor and Senior Vice-Dean of Research, Duke-National University of Singapore Medical School

Source:
Journal reference:

Yu, J., et al. (2020) The functional landscape of patient-derived RNF43 mutations predicts sensitivity to Wnt inhibition. Cancer Research. doi.org/10.1158/0008-5472.CAN-20-0957.

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