The identification of candidate effective combination regimens for pancreatic cancer using the histoculture drug response assay

Eunsung Jun,Yejong Park,Song Lee,Song Cheol Kim,Moon Bo Kim,Ji Sun Lee,Ki Byung Song,Dae Wook Hwang,Woohyung Lee,Robert M Hoffman,Jaewoo Kwon,Jae Hoon Lee

doi:10.1038/s41598-020-68703-x

Abstract

The prognosis for patients with pancreatic cancer is extremely poor, as they are resistant to first line chemotherapy. The long-term goal of this study was to identify effective combination chemotherapy for pancreatic cancer using pancreatic cancer surgical specimens in the histoculture drug response assay (HDRA) based on three-dimensional culture of tumour fragments, which maintains nature tumour histology in vitro. From 2015 to 2017, the HDRA was performed with tumour specimens from 52 pancreatic cancer patients from Asan Medical Hospital. First, combination drug regimens showed higher drug efficacy and less patient variation than single drugs. Initially, 5-Fluorouracil(5-FU)/Belotecan/Oxaliplatinum and Tegafur/Gimeracil (TS-1)/Oxaliplatinum/Irinotecan were found to be effective. Second, we were able to correlate the efficacy of some drugs with tumour stage. Third, when designing new combination regimens containing 5-FU or gemcitabine, we could identify more effective drug combinations. This is the first study to demonstrate usefulness of the HDRA for pancreatic cancer. Using this technique, we could identify novel candidate combination drug regimens that should be effective in treating pancreatic cancer.

Highlights

The prognosis for patients with pancreatic cancer is extremely poor, as they are resistant to first line chemotherapy
Since the desmoplastic stroma acts as a physiological barrier for anticancer drugs, it is essential to consider the desmoplasia of pancreatic cancer in order to improve chemotherapy e fficacy[16,24]
The histoculture drug response assay (HDRA) was developed in 1987 using sponge gel-supported three-dimensional histoculture of tumour fragments from cancer patients[21], which has many advantages including culture of intact tumour fragments which maintain native cancer-cell stroma-cell interaction allowing an in vivo-like environment much superior to 2D culture[25]

Summary

Introduction

The prognosis for patients with pancreatic cancer is extremely poor, as they are resistant to first line chemotherapy. Numerous clinical studies have been performed on pancreatic cancer using a combination of radiation therapy, conventional chemotherapy, or various immunotherapies[11,12,13]. The HDRA can identify effective chemotherapy drugs based on inhibition of tumour viability.

Results

Conclusion