Digestive cancers: mechanisms, therapeutics and management

Abstract

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

Fig. 1

Current therapeutic targets in esophageal squamous cell carcinoma (ESCC). 5-FU 5-fluorouracil, PD-1 programmed cell death protein 1, PD-L1 programmed cell death 1 ligand 1, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, EGFR epidermal growth factor receptor, VEGFR vascular endothelial growth factor receptor. Therapies that are recommended by international guidelines are marked in red. Therapies with preclinical or only low levels of clinical evidence are highlighted in blue

Fig. 2

Current therapeutic targets in gastric cancer and GEJ adenocarcinoma. 5-FU 5-fluorouracil, VEGFR vascular endothelial growth factor receptor, HER2 human epidermal growth factor receptor 2, CLDN18.2 claudin 18.2, PD-1 programmed cell death protein 1, FGFR2b fibroblast growth factor receptor 2b, DKK1 Dickkopf WNT signaling pathway inhibitor 1. Therapies that are recommended by international guidelines are marked in red. Therapies with preclinical or only low levels of clinical evidence are highlighted in blue

Fig. 3

Current therapeutic targets in biliary tract cancer. 5-FU 5-fluorouracil, FGFR2 fibroblast growth factor receptor 2, HER2 human epidermal growth factor receptor 2, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1, PD-L1 programmed cell death 1 ligand 1, NTRK neurotrophic tyrosine receptor kinase, CA19-9 carbohydrate antigen 19-9. Therapies that are recommended by international guidelines are marked in red. Therapies with preclinical or only low levels of clinical evidence are highlighted in blue

Fig. 4

Current therapeutic targets in hepatocellular cancer. VEGFR vascular endothelial growth factor receptor, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1, PD-L1 programmed cell death 1 ligand 1, TGFBR1 transforming growth factor beta receptor 1, GPC3 glypican-3, BCLC Barcelona clinic of liver cancer classification. Therapies that are recommended by international guidelines are marked in red. Therapies with preclinical or only low levels of clinical evidence are highlighted in blue

Fig. 5

Current therapeutic targets in pancreatic cancer. 5-FU 5-fluorouracil, EGFR epidermal growth factor receptor, NTRK neurotrophic tyrosine receptor kinase. Therapies that are recommended by international guidelines are marked in red. Therapies with preclinical or only low levels of clinical evidence are highlighted in blue

Fig. 6

Current therapeutic targets in colorectal cancer. 5-FU 5-fluorouracil, VEGFR vascular endothelial growth factor receptor, HER2 human epidermal growth factor receptor 2, EGFR epidermal growth factor receptor, PD-1 programmed cell death protein 1, PD-L1 programmed cell death 1 ligand 1, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, NTRK neurotrophic tyrosine receptor kinase. Therapies that are recommended by international guidelines are marked in red. Therapies with preclinical or only low levels of clinical evidence are highlighted in blue

Fig. 7

Novel therapeutic developments in digestive cancers. A selection of therapeutic development as well as specific application cases are shown. ADC antibody-drug conjugates, HER2 human epidermal growth factor receptor 2, CLD18.2 claudin 18.2, STING stimulator of interferon genes, LAG3 lymphocyte-activation gene 3, VISTA V-domain Ig suppressor of T cell activation, PROTAC proteolysis-targeting chimera, FGFR2b fibroblast growth factor receptor 2b, GPC3 glypican-3