Abstract 108: Efficiency improvement niche factors in drug susceptibility test using two dimension organoids derived from colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is one of the leading cause of cancer-related death of world wide. About one in five patients with CRC has metastatic disease, and it is the major cause of death. Metastasis of the primary tumor is directly related to the patient survival. Systemic chemotherapy is the standard approach to treat the metastatic CRC (mCRC), and there are several protocols currently used for the mCRC, and the median survival time has increased by the systemic chemotherapy such as irinotecan, oxaliplatin, cetuximab and bevacizumab. However, the effect of the chemotherapy depends on the character of the individual tumor; we still have many patients who could not receive any benefit from the systemic chemotherapy. Therefore, we examined the individual drug sensitivity using organoids derived from each patient to predict the clinical efficacy of the chemotherapeutic drugs. We established a novel culture method for the patient’s tumor, named “two-dimension organoids (2DO)” using surgically resected specimens harboring phenotypic heterogeneity as an ideal patient’s tumor model. The gene expression of these organoids was similar to the each parental tumor, and they constructed a ductal structure of the tumor in the xenograft model. The previous study using 2DO allowed us to predict the clinical efficacy of chemotherapeutic drugs. However, all patients who underwent surgical resection do not need the chemotherapy. We examined the culture method and evaluated additional niche factors to establish 2DO efficiently from small-size samples, such as biopsy samples. Inflammation is a well-known risk factor for the development of colorectal cancer and several cytokines play the important roles in inflammatory reactions. Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine which is predominantly produced by macrophages as well as tumor cells. It was reported to promote tumor progression in some cancers where TNF-alpha activates the NF-κB pathway, which represents the act in the oncogenesis and cancer cell proliferation. The relationship between TNF-alpha and 2DO growth was examined in surgically resected specimens and endoscopic biopsies (n=15, each). The growth rates of 2DOs with TNF-alpha were significantly faster than the others without TNF-alpha (P=0.039). Using these 2DO cultured with TNF-alfa, the correlations for the chemotherapeutic drugs were observed between the 2DO and clinical outcomes of chemotherapy. In conclusion, TNF-alpha supports the growth of 2DO even from the small-size samples, resulting in the useful material for the precision medicine. Citation Format: Kazuhiro Saso, Norikatsu Miyoshi, Masaru Sasaki, Shiki Fujino, Hidekazu Takahashi, Naotsugu Haraguchi, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki. Efficiency improvement niche factors in drug susceptibility test using two dimension organoids derived from colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 108.