Multicellular Modelling of Difficult-to-Treat Gastrointestinal Cancers: Current Possibilities and Challenges

Abstract

Cancers affecting the gastrointestinal system are highly prevalent and their incidence is still increasing. Among them, gastric and pancreatic cancers have a dismal prognosis (survival of 5–20%) and are defined as difficult-to-treat cancers. This reflects the urge for novel therapeutic targets and aims for personalised therapies. As a prerequisite for identifying targets and test therapeutic interventions, the development of well-established, translational and reliable preclinical research models is instrumental. This review discusses the development, advantages and limitations of both patient-derived organoids (PDO) and patient-derived xenografts (PDX) for gastric and pancreatic ductal adenocarcinoma (PDAC). First and next generation multicellular PDO/PDX models are believed to faithfully generate a patient-specific avatar in a preclinical setting, opening novel therapeutic directions for these difficult-to-treat cancers. Excitingly, future opportunities such as PDO co-cultures with immune or stromal cells, organoid-on-a-chip models and humanised PDXs are the basis of a completely new area, offering close-to-human models. These tools can be exploited to understand cancer heterogeneity, which is indispensable to pave the way towards more tumour-specific therapies and, with that, better survival for patients.

The impact of antibiotic use in gastrointestinal tumors treated with immune checkpoint inhibitors: systematic review and meta-analysis

“…The incorporation of research from various nations expands the viewpoint and enhances the applicability of the findings. The meta-analysis’s preponderance of HCC cases highlights the pressing need for efficient treatment options for this difficult-to-treat illness ( 26 , 27 ). The high percentage of patients with advanced-stage cancer emphasizes how crucial it is to investigate cutting-edge treatment options, like ICIs, in order to enhance patient outcomes.…”

Pancreatic cancer environment: from patient-derived models to single-cell omics

“…It has been documented that patient-derived xenograft models exhibit a higher fidelity to the clinical response to therapy compared to conventional xenograft models. 23 In vitro cell lines and mouse allografts are inadequate for meeting the preclinical needs. 19 Furthermore, the utilization of humanized patient-derived xenograft models presents a highly effective platform for the examination of the intricate interactions occurring between the immune system and the microbiome.…”

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

“…Among gastrointestinal tumors, the survival rate of gastric and pancreatic cancers is 5%−20%, most GCs are diagnosed in the late stage because there are no obvious symptoms in the early stage, leading to a high mortality rate. [234][235][236][237][238] Epigenetic changes are valuable biomarkers for GC prognosis. Jang et al found that the trimethylated state of H3K9 is highly expressed and positively correlated with tumor staging.…”

“…Among gastrointestinal tumors, the survival rate of gastric and pancreatic cancers is 5%−20%, most GCs are diagnosed in the late stage because there are no obvious symptoms in the early stage, leading to a high mortality rate. 234 , 235 , 236 , 237 , 238 Epigenetic changes are valuable biomarkers for GC prognosis. Jang et al.…”