Patient-derived organoid models help define personalized management of gastrointestinal cancer

Abstract

Background: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models.Methods: A PubMed search was conducted to identify relevant articles. An overview of the literature and published protocols is presented, and the implications of these models for patients with cancer, surgeons and oncologists are explained.Results: Organoid culture methods have been established for healthy and diseased tissues from oesophagus, stomach, intestine, pancreas, bile duct and liver. Because organoids can be generated with high efficiency and speed from fine-needle aspirations, biopsies or resection specimens, they can serve as a personal cancer model. Personalized treatment could become a more standard practice by using these cell cultures for extensive molecular diagnosis and drug screening. Drug sensitivity assays can give a clinically actionable sensitivity profile of a patient's tumour. However, the predictive capability of organoid drug screening has not been evaluated in prospective clinical trials. Conclusion:High-throughput drug screening on organoids, combined with next-generation sequencing, proteomic analysis and other state-of-the-art molecular diagnostic methods, can shape cancer treatment to become more effective with fewer side-effects.

High‐throughput screening in colorectal cancer tissue‐originated spheroids

“…Inter‐patient variations in sensitivity to therapeutics are a challenging issue in clinical practice, making it increasingly important to obtain tumor samples from individual cancer patients for both development of therapeutics and personalized medicine. To determine the portion of the population in which a drug will be effective and to identify biomarkers to demarcate potential responders, it is essential to develop systems in which drugs can be tested on materials retaining the heterogeneous characteristics of the original disease …”

“…Over the past decade, primary culture has been significantly improved by overcoming complicated procedures, poor reproducibility and uncontrolled co‐existence of various cell types . Modern cultures are expected to retain the characteristics of parental patient tumors, including drug sensitivity.…”

Precision Medicine in Oncology: In Vitro Drug Sensitivity and Resistance Test (DSRT) for Selection of Personalized Anticancer Therapy

“…Tumor organoids can be passaged, expanded, and cryopreserved similar to cell lines. They can be generated from fine‐needle aspirations or surgically removed tumor within few weeks and used for molecular profiling of a tumor, as well as for individualized therapeutic screening (pharmacotyping) . There is an increasing number of studies where patient‐derived tumor organoids are used for DSRT and other precision medicine studies, some of which are described below and summarized in Table .…”

“…There are few studies showing positive correlation between DSRT performed on tumor spheroid/organoid cultures and short‐term clinical response of the patients . However, there is no study yet comparing long‐term survival rate of patients, treated with therapy recommended based on results of DSRT and treated with conventional therapy …”

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

“…Despite tremendous advancements in our understanding of the initiation and progression of pancreatic cancer from premalignant precursor lesions to fully invasive and systemically metastatic disease states on the molecular level, progress in identifying and clinically exploiting novel targets for therapeutic intervention has been hampered by the sheer complexity (with each pancreatic cancer cell carrying on average more than 60 mutations) and intra- as well as interindividual variability in the patterns of genetic alterations underlying pancreatic carcinogenesis [1,6,7]. Another boost in target discovery and translational research came from recent advancements in relevant preclinical in vitro and in vivo model systems of pancreatic cancer, including advanced xenografts models, genetically engineered murine model systems as well as low-passage cell lines, three-dimensional cell cultures, and ex vivo and organoid models [8,9,10,11,12,13,14,15,16,17,18,19,20,21]. …”