In 2009 a landmark paper was published by the Hans Clevers group from the Hubrecht Institute and University Medical Center Utrecht (UMC Utrecht) in the Netherlands, which first demonstrated the long-term culture of intestinal stem cells giving rise to functional mini-organs in a dish, also named “organoids” 1. Two years later, the Clevers group was able to culture organoids from colorectal cancer and Barrett’s esophagus patients 2. Organoids would soon dominate the scientific field and earn Nature Methods’ distinction of Method of the Year in 2017 3.
As a PhD student at the UMC Utrecht, I am privileged to be part of this fruitful environment, where translational research using Organoid Technology is prevalent and the focus of my PhD research. Clinicians from the UMC Utrecht, Princess Maxima Center for pediatric oncology (PMC) and Wilhelmina Children’s Hospital (WKZ) and researchers from the Hubrecht Institute and Hubrecht Organoid Technology (HUB) collaborate on leading research projects, resulting in many new organoid types and clinical trials to examine how organoids can be used to improve treatment for patients 4–8. To facilitate rapid and standardised tissue acquisition and processing, Utrecht Platform for Organoid Technology (UPORT) is available for researchers and clinicians.
Along with the rest of the world, the research and clinical community in the Netherlands were hit hard by the pandemic. Laboratories were closed and clinical trials were paused in order to accommodate the influx of COVID-19 patients. With the vast literature available, this was an opportunity for us to critically review the available evidence. Can we use organoids to predict treatment response in cancer patients? Which barriers should be overcome to accelerate the transition of organoids to the clinic? The results of this effort were published in the recent edition of npj Precision Oncology (https://rdcu.be/ciwPE) 9.
In our systematic review, we identified 17 oncological studies which reported data regarding organoid-based drug screen results and their predictive value and association with the patient’s response in the clinic. We focussed on 3 aspects to assess organoids as a predictive biomarker: their analytical validity, clinical validity and clinical utility and we offered perspectives for future research.
The currently available results offer an optimistic perspective that testing of individualized tumour response on organoids have clinical validity as a predictive biomarker for cancer patients. The pooled sensitivity and specificity for discriminating patients with a clinical response through organoid-based screening were 0.81 (95%C.I. 0.69-0.89) and 0.74 (95%C.I. 0.64-0.82), respectively. This is an estimation since not all studies reported results which could be used for the pooled analysis and not all studies used a pre-defined index test when analyzing results. The current evidence is strongest for colorectal cancer patients, with larger studies showing a correlation between organoid-based drug screen results and systemic therapy/radiation treatment response and with smaller studies showing promising descriptive results for other tumour and treatment types. Prior to being able to implement organoid-based drug screens in the clinic, the results should be validated in similar, larger patient cohorts. The current challenge is to prove that organoid-based individualized tumour response testing is feasible, by optimizing organoid establishment rates and time to obtaining organoid-based screening results. The results regarding clinical validity of organoids as a predictive biomarker are promising and ultimately the clinical utility should be proven by demonstrating that organoid-based individualized tumour response testing is cost effective, leads to improved clinical decision making and offers clinical benefit for patients. If organoids can be established for the majority of patients within a feasible time frame, this potential predictive biomarker can facilitate personalized treatment for a large group of patients for whom there is a great need for valid predictive biomarkers.
Ongoing studies from our group (led by Jeanine Roodhart, medical oncologist UMC Utrecht) will examine the identified future perspectives. This includes a prospective proof-of-concept clinical trial (OPTIC) to examine if organoids can predict treatment response in metastatic colorectal cancer patients and a retrospective study of organoids derived for the HUB-Cancer Biobank (both are a collaboration with the HUB and UMC Utrecht). Recently, an investigator driven phase I/II clinical trial (RASTRIC), designed by the UMC Utrecht (Jeanine Roodhart, Hugo Snippert and Hans Bos), was started to evaluate a novel triple combination treatment for RAS-mutated metastatic colorectal cancer patients which was discovered using organoid research for drug development. Through our ongoing research we aim to clarify how organoids can be incorporated in the clinic in order to facilitate personalized treatment for oncology patients.
- Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
- Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).
- Method of the Year 2017: Organoids. Nat. Methods 15, 1 (2018).
- Boj, S. F. et al. Organoid Models of Human and Mouse Ductal Pancreatic Cancer. 324–338 (2015). doi:10.1016/j.cell.2014.12.021
- de Witte, C. J. et al. Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses. Cell Rep. 31, 107762 (2020).
- Driehuis, E. et al. Oral Mucosal Organoids as a Potential Platform for Personalized Cancer Therapy. Cancer Discov. 9, 852–871 (2019).
- Sachs, N. et al. A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity. Cell 172, 373–386.e10 (2018).
- Calandrini, C. et al. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity. Nat. Commun. 11 (2020).
- Wensink, G.E. et al. Patient-derived organoids as a predictive biomarker for treatment response in cancer patients. npj Precis. Onc. 5, 30 (2021).