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Multicellular Modelling of Difficult-to-Treat Gastrointestinal Cancers: Current Possibilities and Challenges
Sarah K Hakuno1,2, Ellis Michiels2,3, Eleonore B Kuhlemaijer1
1Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
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.
Insights
Patient-derived organoids (PDO) and patient-derived xenografts (PDX) offer promising preclinical models for difficult-to-treat gastric and pancreatic cancers. These models advance personalized therapies and improve patient survival by enabling better understanding of cancer heterogeneity.
Area of Science:
- Gastrointestinal oncology
- Translational cancer research
- Preclinical cancer modeling
Background:
- Gastric and pancreatic cancers, particularly pancreatic ductal adenocarcinoma (PDAC), have poor prognoses and high incidence rates.
- There is a critical need for novel therapeutic targets and personalized treatment strategies for these difficult-to-treat cancers.
- Reliable preclinical models are essential for identifying therapeutic targets and testing interventions.
Purpose of the Study:
- This review discusses the development, advantages, and limitations of patient-derived organoids (PDO) and patient-derived xenografts (PDX) for gastric and pancreatic ductal adenocarcinoma.
- To highlight the potential of these models in advancing personalized cancer therapies.
- To explore future opportunities in developing advanced preclinical models.
Main Methods:
- Discussion of first and next-generation multicellular PDO and PDX models.
- Review of current literature on PDO and PDX models in gastric and pancreatic cancer research.
- Exploration of emerging technologies like PDO co-cultures, organoid-on-a-chip, and humanized PDXs.
Main Results:
- PDO and PDX models serve as patient-specific avatars in preclinical settings.
- These models facilitate the exploration of novel therapeutic strategies for challenging gastrointestinal cancers.
- Advanced models like co-cultures and organoid-on-a-chip offer more human-relevant preclinical systems.
Conclusions:
- PDO and PDX models are instrumental in understanding cancer heterogeneity and developing tailored therapies.
- Future developments in preclinical modeling promise to enhance our ability to treat gastric and pancreatic cancers.
- These advanced models hold the potential to significantly improve patient survival rates.
