Clinical translation of patient-derived tumour organoids- bottlenecks and strategies

(2022) 10:10 Foo et al. Biomarker Research https://doi.org/10.1186/s40364-022-00356-6 Open Access REVIEW Clinical translation of patient‑derived tumour organoids‑ bottlenecks and strategies Malia Alexandra Foo1†, Mingliang You2,3†, Shing Leng Chan1,4, Gautam Sethi5,6, Glenn K. Bonney4,5, Wei‑Peng Yong1,7, Edward Kai‑Hua Chow1,5,6, Eliza Li Shan Fong1,8, Lingzhi Wang1,5,6* and Boon‑Cher Goh1,5,6,7* Abstract Multiple three-dimensional (3D) tumour organoid models assisted by multi-omics and Artificial Intelligence (AI) have contributed greatly to preclinical drug development and precision medicine. The intrinsic ability to maintain genetic and phenotypic heterogeneity of tumours allows for the reconciliation of shortcomings in traditional cancer mod‑ els. While their utility in preclinical studies have been well established, little progress has been made in translational research and clinical trials. In this review, we identify the major bottlenecks preventing patient-derived tumour orga‑ noids (PDTOs) from being used in clinical setting. Unsuitable methods of tissue acquisition, disparities in establish‑ ment rates and a lengthy timeline are the limiting factors for use of PDTOs in clinical application. Potential strategies to overcome this include liquid biopsies via circulating tumour cells (CTCs), an automated organoid platform and opti‑ cal metabolic imaging (OMI). These proposed solutions accelerate and optimize the workflow of a clinical organoid drug screening. As such, PDTOs have the potential for potential applications in clinical oncology to improve patient outcomes. If remarkable progress is made, cancer patients can finally benefit from this revolutionary technology. Keywords: Tumour, Organoid, Precision, Medicine, Three-Dimensional (3D) Introduction Cancer is a leading cause of death globally, responsible for 1 in every 6 deaths, and an approximate 10 million deaths in 2020 alone [1]. According to the World Health Organization (WHO), the most common causes of mortality were lung, colorectal, liver, stomach and breast cancer. Despite being the most frequently diagnosed cancers, current treatment remains ineffective in achieving curative effects in certain patients, causing their demise. This can be attributed to the “one-size-fits-all” standard of care for anti-cancer treatment which does not account for heterogeneity, rendering it ineffective and *Correspondence: ; † Malia Alexandra Foo and Ming Liang You contributed equally to this work. 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore Full list of author information is available at the end of the article obsolete. Inter-patient heterogeneity and intra-patient heterogeneity are the key reasons for therapeutic failure for standardized anti-cancer treatment [2, 3]. Standard chemotherapy drugs may not be effective for all patients for this reason. The rise of precision medicine is an emerging approach to the targeted selection of optimal treatment options based on each individual’s genes, environment and lifestyle. Precision medicine, in the context of cancer treatment, is to identify effective therapeutic strategies specific for every patient [4], by using targeted therapies that are less invasive and morbid than standard treatment regimens yet achieving good outcomes. Organoid technology is one that holds significant potential in realizing this goal. Cancer organoids are revered for their ability to retain the heterogeneity and fundamental morphology of patient’s tumour [4]. This was not © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Foo et al. Biomarker Research (2022) 10:10 realized by two-dimensional (2D) cell culture lines, the current model used for in vitro cancer modelling and drug screening [5]. 2D cell cultures have been vital in cancer research, but, their main limitation lies in their inaccuracy in replicating cancer cells in vivo [6]. Their 2D structures causes changes in polarity, morphology and method of division as well as disturbances in interactions between the cellular and extracellular environments. Most importantly, they are unable to accurately Page 2 of 18 recapitulate the complex and dynamic nature of cancer, especially drug resistance mechanisms which remains the principal limiting factor to achieving cures in patients with cancer [7]. Fundamentally, they are inaccurate representations of in vivo tumours, but are used widely due to their ease of proliferation, low-cost maintenance, amenability to performance of functional tests [8] (Fig. 1A). Another promising cancer model is the patientderived xenografts (PDXs). PDXs are able to diligently Fig. 1 Comparison of Cell Lines, Patient-Derived Xenografts (PDXs) and Patient-Derived Tumour Organoids (PDTOs). A: 2D cell line model; B: Patient-Derived Xenografts (PDXs) model; C: Patient-Derived Tumour Organoids (PDTOs) model Foo et al. Biomarker Research (2022) 10:10 recapitulate the biological characteristics of the human tumour, but are extremely time consuming and expensive to utilize [9]. Furthermore, PDXs also demonstrate the ability to undergo murine-specific tumour evolution, [10] and raises various ethical concerns regarding the use of animal models for experimentation [11]. For these reasons, PDXs are unsuitable for high-throughput drug screening (HTS) and remain largely in the laboratory for research. (Fig. 1B). As a result, tumour organoids, for their ability to reconcile the shortcomings of current cancer models holds great promise for optimization of preclinical drug discovery. Tumour organoids are less expensive, time-consuming and resource-intensive than PDXs [12]. Furthermore, tumour organoids are a suitable model which both, reflects the physiological features of an actual patient’s cancer [13] as well as are compatible with the standard procedures in HTS drug screening in the pharmaceutical industry (Fig. 1C). While the utility of tumour organ (...truncated)