Gastric Cancer Organoids in the Screening of Neoadjuvant Drugs

Overview

Gastric cancer is an important disease burden that threatens human health. Due to the complex biological characteristics of gastric cancer, the research on gastric cancer is still at a low level. Organoid technology is a breakthrough technology in cancer research. Gastric cancer organoid is a good model for gastric cancer research by three-dimensional culture of tumor cells in vitro, which simulates the spatial morphology and structure of tumors in vivo while preserving the biological characteristics of tumor cells. At present, gastric cancer organoid models have shown great advantages in many fields, such as the mechanism of gastric cancer development, tumor drug resistance, large-throughput chemotherapy drug screening, novel therapeutic target searching, and preclinical validation of novel drugs. In the current clinical trial, investigators cultured organoids from gastroscopic biopsy tissue of gastric cancer patients, and compared the organoids with the sampled tumors, including immunohistochemical indicators (Ki67+/CK20+/CDX2+), WES sequencing results. At the same time according to the guidelines. The recommended treatment plan is to compare the organoid model drug screening results with the clinical drug sensitivity.

There is an important clinical problem in neoadjuvant chemotherapy, adjuvant chemotherapy and palliative chemotherapy for locally advanced gastric cancer, that is, insufficient effectiveness of chemotherapy. Among the patients with neoadjuvant therapy, some patients will have pathological complete remission, and the prognosis of these patients is better than that of other patients. However, not all patients have a good pathological response after neoadjuvant chemotherapy, although many studies have reported uneven response rates and individual differences in patient sensitivity to chemotherapy drugs. At present, investigators still lack adequate methods to predict the effectiveness of chemotherapy and adjust treatment strategies in time to achieve the best clinical outcomes. In addition, targeted therapy and immunotherapy are widely used in clinical practice, and gene sequencing is performed on tumor samples of patients to guide the selection of targeted drugs. However, according to clinical data feedback, this method has many limitations, for example, patients with a targeted gene mutation of a targeted drug cannot respond to the drug, while patients without the targeted gene mutation can respond very well to the drug. The reason is that the sequencing results based on some known proto-oncogenes or tumor suppressor genes cannot fully reflect the genomic background of the patient, including some unknown cancer-related genes, and even non-coding protein sequences play important regulatory roles in the process of cancer. Therefore, how to quickly select the most effective drug for this patient among the numerous cancer targeted drugs on the market is the decisive factor for the success or failure of cancer precision medicine. In recent years, an important breakthrough in basic tumor research is the tumor organoid technology established in vitro, which directly obtains tumor tissue from patients, rapidly expands in vitro, and forms organoids with a high physiological and pathological state similar to the original tissue in a short time. This organoid is a three-dimensional assembly of cells containing more than one cell type. Since the cultured organoids are derived from the patient's own tumor tissue, they can well retain various characteristics of the tumor tissue in situ. Compared with the traditional 2D cell line culture, organoids are directly derived from patients, can retain the patient's genomic information and epigenetic information, maintain the heterogeneous components of the original tumor, and have a 3D structure that is more in line with the conditions in vivo, so it is more representative. Compared with the animal transplant tumor model derived from patients, organoids have the advantages of low cost, high success rate, short culture cycle and easy operation. In general, tumor organoids combine the advantages of 2D cell line culture and animal transplant tumor models, which can not only fully reflect the genetic information and tumor phenotype of patients, but also ensure the heterogeneity of tumors, and have high economic benefits. Therefore, they are favored in scientific research and clinical practice, and are effective tools for evaluating drug response and screening drugs. There are already some of the top cancer research institutes in the world, National Cancer Institute (Netherlands), Cancer Research UK (UK) and the Wellcome Trust Sanger Institute (UK) are working together to build a sample bank of various Tumor organoids that are already being used in precision medicine for cancer patients. As such, investigators designed a single-center prospective, observational clinical trial for patients with locally advanced gastric cancer, aiming to explore the application of gastric cancer organoids in chemotherapy drug screening, so as to improve the efficacy of neoadjuvant chemotherapy for gastric cancer and provide a basis for the precision treatment of neoadjuvant therapy for gastric cancer.