The application of pancreatic cancer organoids for novel drug discovery

ABSTRACT

Introduction

Pancreatic ductal adenocarcinoma presents with a dismal prognosis. Personalized therapy is urgently warranted to overcome the treatment limitations of the ‘one-size-fits-all’ scheme. Organoids have emerged as fundamental novel tools to study tumor biology and heterogeneity, hence overcoming limitations of other model systems by better-reflecting tissue heterogeneity and recapitulating in-vivo processes. Besides their crucial role in basic research, they have evolved as tools for translational drug discovery and patient stratification.

Areas covered

This review highlights the achievements of an organoid-based drug investigation and discovery. The authors present an overview of studies using organoids for drug testing. Further, they pinpoint studies correlating the in vitro prediction of organoids to the actual patient`s response. Furthermore, the authors describe novel model systems and take a thorough overlook of microfluidic chips, synthetic matrices, multicellular systems, bioprinting, and stem cell-derived pancreatic organoid systems

Expert opinion

Organoid systems promise great potential for future clinical applications. Indeed, they may be implemented into informed decision-making for guiding therapies. However, validation by randomized trials is mandatory. Additionally, organoids in combination with other cellular compartments may be exploited for drug discovery by studying niche-tumor interaction. Yet, several precautions must be kept in mind, such as standardization and reproducibility.

KEYWORDS:

• assembloids
• drug discovery
• microfluidic chips
• multicellular systems
• organoids
• personalized medicine
• pancreatic cancer

Article highlights

• Pancreatic cancer patient-derived organoids have been intensely characterized and provide immense potential for drug response prediction.

• State-of-the-art studies retrospectively correlated organoid sensitivity to the clinical response.

• Mid- to large-scale screenings for different (experimental) drugs in many different organoid lines are feasible in a reasonable setting.

• Novel organoid model systems include microfluidic chips, synthetic hydrogels, and multicellular assembloids and might further advance our understanding of tumor biology.

• Multicellular-based models enable the study of tumor-niche interactions and provide a platform to investigate specific inhibitors for stroma-dependent tumor propagation signals.

Acknowledgments

The authors thank Ninel Azoitei for critically assessing the manuscript and giving input.

Declaration of Interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was primarily funded by the Deutsche Forschungsgemeinschaft (DFG) “Sachbeihilfe“ KL2544/7-1 and ‘Heisenberg-Programm’ KL2544/6-1 to A Kleger. Further funding was acquired by A Kleger from the German Cancer Aid (AK70114761). MK Melzer has received additional funding in the Clinician-Scientist-Program of Ulm University. A.K. is speaker of an Else Kröner Research School for Physicians. MK Melzer and Y Resheq are clinician scientists within the Else Kröner Research School for Physicians.