Sulfatases 1 and 2: Potential Therapeutic Targets in Intrahepatic Cholangiocarcinoma?

By: Celeste L. Dixon
Posted: Friday, December 9, 2022

Preclinical research has uncovered a novel mechanism that may potentially enhance the treatment of intrahepatic cholangiocarcinoma, in which the effect of chemotherapy has been limited. Using real-time polymerase chain reaction and immunohistochemistry, Jianbo Huang, MD, of the Mayo Clinic, Rochester, Minnesota, and colleagues found that the expression of SULF1 and SULF2—which are heparan sulfate proteoglycan editing sulfatases—is greater in intrahepatic cholangiocarcinoma than in normal bile duct tissues. In this cancer, they discovered, the sulfatases promote malignancy through EGFR activation, and their overexpression is associated with shorter overall and recurrence-free survival.

The team tested the possible therapeutic value of “targeting this newly identified SULF1/2-EGFR axis for intrahepatic cholangiocarcinoma [by] using an anti-SULF2 monoclonal antibody, 5D5, in combination with an anti-EGFR monoclonal antibody, cetuximab, in a xenograft model,” explained the team in a presentation at the 2022 American Association for the Study of Liver Disease (AASLD) Annual Meeting (Abstract 210). They sought the answer by using Western immunoblotting, immunofluorescence, and co-immunoprecipitation. And, they found that the knockdown of SULFs “significantly decreased intrahepatic cholangiocarcinoma cell proliferation.” Response was independent of KRAS mutation status.

According to Dr. Huang and co-investigators, SULFs promote EGFR activation by enhancing HB-EGF release from CD44 and CD9; moreover, SULFs-mediated EGFR activation seems to modulate response to cetuximab in intrahepatic cholangiocarcinoma. “Finally, the anti-SULF2 antibody, 5D5, defined the translational value of targeting SULF2 in intrahepatic cholangiocarcinoma, showing profound tumor growth inhibition in combination with cetuximab or chemotherapy,” they explained.

Disclosure: The study authors’ disclosure information can be found at onlinelibrary.wiley.com.

2022 AASLD Annual Meeting

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