br This study tests the potential of gastric cancer derived
This study tests the potential of gastric cancer–derived organoids as an approach to predict in vivo tumor responses. Effect of standard-of-care therapies on organoids was correlated with results of in vivo treatment. The data suggest that patient-derived organoids will be useful in developing individualized therapies.
BACKGROUND & AIMS: Our goal was to develop an initial study for the proof of concept whereby gastric cancer organo-ids are used as an approach to predict the tumor response in individual patients.
METHODS: Organoids were derived from resected gastric cancer tumors (huTGOs) or normal M3814 (nedisertib) tissue collected from sleeve gastrectomies (huFGOs). Organoid cultures were treated with standard-of-care chemotherapeutic drugs corresponding to patient treatment: epirubicin, oxaliplatin, and 5-fluorouracil. Organoid response to chemotherapeutic
treatment was correlated with the tumor response in each patient from whom the huTGOs were derived. HuTGOs were orthotopically transplanted into the gastric mucosa of NOD scid gamma mice.
RESULTS: Whereas huFGOs exhibited a half maximal inhibitory concentration that was similar among organoid lines, divergent responses and varying half maximal inhibitory concentration values among the huTGO lines were observed in response to chemotherapeutic drugs. HuTGOs that were sensitive to treat-ment were derived from a patient with a near complete tumor response to chemotherapy. However, organoids resistant to treatment were derived from patients who exhibited no response to chemotherapy. Orthotropic transplantation of organoids resulted in the engraftment and development of human adenocarcinoma. RNA sequencing revealed that huTGOs closely resembled the patient’s native tumor tissue and not commonly used gastric cancer cell lines and cell lines derived from the organoid cultures.
CONCLUSIONS: The treatment of patient-derived organoids alongside patients from whom cultures were derived will
Keywords: Stomach; Organoids; Gastroids; Chemotherapy.
Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths, with a 5-year survival rate of only 29%.1 The incidence of gastric cancer is 4 times more common in Japan than in the United Kingdom and United States and occurs at a younger age.2 Because of the poor response of gastric cancer to various existing treatments, there is a need for approaches to predict the efficacy of therapy for individuals. We report here the generation of patient-derived gastric cancer organoids that may be useful for the prediction
of patient responses to chemotherapy treatment. Randomized data have clearly established that surgery
alone for the treatment of gastric cancer results in reduced survival and increased recurrence rates when compared with multimodality therapy.1 A current limitation for the treatment of gastric cancer is the lack of a reliable approach to identify which treatment options are most effective for each individual patient. For example, human epidermal growth factor receptor 2 (HER2) expression is used as a biomarker for the prediction of response to anti-HER2 monoclonal antibody trastuzumab in patients with meta-static gastric cancer.3 Currently, HER2 expression is deter-mined by immunohistochemistry or by the detection of HER2 gene amplification by fluorescence in situ hybridiza-tion.4,5 However, because of tumor heterogeneity these approaches may represent inaccuracy in HER2 testing.6 Thus, further approaches are required to improve reli-ability of HER2 testing to ensure that patients receive the appropriate therapy for their individual disease.
Although cancer cell lines have proven valuable in the investigation of fundamental cancer research mechanisms, these models have the significant disadvantage of bearing little resemblance to the intended patient tumor.7–11 The development of high-throughput analytical methods now enables us to address the clinical relevance of these human cancer-derived cell lines. At the genomic level, driver mutations may be retained within cancer cell lines. How-ever, several studies reveal a drift at the transcriptomic level, demonstrating that cancer cell lines carry more resemblance to each other rather than to the clinical samples from which they were originally derived.9,10 Our study reports the use of three-dimensional organoids as a potential tool used for the prediction of targeted therapies for gastric cancer patients.
Individual Patient-Derived Gastric Cancer Organoids Display Unique Responses to Chemotherapeutic Drugs and Targeted Therapy
We generated an initial bank of gastric cancer organoids from tumors obtained from 7 patients (Table 1). For each patient from whom the organoids were derived, patient