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Improving Cholangiocarcinoma Subtype Classification Unveils Therapeutic Opportunities

Intrahepatic cholangiocarcinomas (iCC) pose a diagnostic and treatment challenge due to their rarity and inter/intrapatient heterogeny. In order to improve outcomes for patients with iCC, a team of researchers from the Republic of Korea’s National Cancer Center, Hanyang University, Korea Basic Science Institute, and the Korea Research Institute of Bioscience and Biotechnology, as part of the National Cancer Institute’s International Cancer Proteogenome Consortium (ICPC), has endeavored to develop a deeper understanding of the tumor microenvironment in iCC through multiomic analyses. Their investigation, spanning genomics, transcriptomics, proteomics, metabolomics, and phosphoproteomics, meticulously scrutinized a cohort of 102 treatment-naïve samples from patients with iCC.

The comprehensive analysis unveiled three clinically-supported iCC subtypes: stem-like, poorly immunogenic, and metabolism. The stem-like subtype, characterized by a distinct molecular profile, emerged as a focal point for therapeutic exploration. For this subtype, the identification of a potential target for treatment in the relationship between NCT-501 (ALDH1A1 inhibitor) and nanoparticle albumin-bound–paclitaxel marks a significant breakthrough.

Moreover, the researchers delved into oncometabolite dysregulations within iCC, revealing differences between the two subtypes in metabolic enzyme expression as well as formaldehyde accumulation in the metabolism subtype. This line of investigation established associations between these metabolic features and clinical outcomes and suggests that tailored treatment approaches accounting for the metabolic signatures of individual iCC subtypes may be feasible.

The poorly immunogenic subtype was found to have a distinctive immunological landscape characterized by non–T-cell tumor infiltration. Further investigation is necessary to understand the interplay between the tumor microenvironment and immune response, which will be pivotal for devising effective therapeutic strategies for those with a poorly immunogenic iCC profile.

In conclusion, this study goes beyond conventional genomic approaches, offering a more complete understanding of the molecular makeup of iCC. This knowledge will serve as a foundation for the development of novel therapeutic strategies and precision medicine approaches to address clinical challenges faced in the treatment of iCC.