Globo H ceramide confers chemoresistance and poor prognosis to advanced gallbladder cancer via A2AR/cAMP/PKA pathway

TL;DR

Globo H ceramide helps gallbladder cancer resist chemotherapy, but targeting it with specific treatments may improve outcomes.

Contribution

This study identifies Globo H ceramide as a driver of chemoresistance in gallbladder cancer and proposes targeting it to enhance chemotherapy effectiveness.

Findings

High Globo H expression correlates with shorter survival in gallbladder cancer patients receiving gemcitabine.

Targeting Globo H with mAb VK9 or vaccines improves chemotherapy efficacy in preclinical models.

Globo H promotes chemoresistance via A2AR/cAMP/PKA-mediated ABCG2 upregulation.

Abstract

Gallbladder cancer (GBC) has poor prognosis, is primarily treated with gemcitabine-based chemotherapy, which is limited by gemcitabine correlates with GBC progression. This study investigate the role of Globo H ceramide (GHCer) in GR and explore whether targeting Glob H could overcome resistance.

Globo H expression was assessed by immunohistochemistry in 81 GBC samples. GHCer-induced GR and ABCG2 upregulation were assessed in GBC cell lines, patient-derived xenograft (PDX), and a thioacetamide (TAA)-induced rat cholangiocarcinoma model. A2AR/cAMP/PKA signaling involvement was examined using inhibitors and siRNA. The efficacy of anti-Globo H antibody (mAb VK9) or vaccine (OBI-833/OBI-821) combined with gemcitabine was evaluated in vitro and in vivo. Immune responses were assessed by ELISA and multiplex immunohistochemistry.

High Globo H expression correlated with shorter survival in GBC patients receiving gemcitabine. GHCer promoted GR via A2AR/cAMP/PKA-mediated ABCG2 upregulation, which was reversed by mAb VK9 or pathway inhibition. mAb VK9 or OBI-833/821 enhanced gemcitabine efficacy in GBC PDX and TAA cholangiocarcinoma models. OBI-833/821 induced anti-Globo H IgG/IgM, reduced Foxp3⁺ Tregs, and increased CD161⁺ NK cells in TAA model. A compassionate clinical use of 833/821 led to stable disease.

GHCer promotes GR by upregulating ABCG2 via A2AR/cAMP/PKA signaling. Targeting Globo H may improve chemotherapy response in GBC.

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