Ex vivo tissue slice culture system to measure drug-response rates of hepatic metastatic colorectal cancer

Steve Z Martin,Nina Hörner,Katrin E Tagscherer,Daniel C Wagner,David Horst,Wilfried Roth,Hauke Lang

doi:10.1186/s12885-019-6270-4

Abstract

BackgroundThe lack of predictive biomarkers or test systems contributes to high failure rates of systemic therapy in metastasized colorectal carcinoma, accounting for a still unfavorable prognosis. Here, we present an ex vivo functional assay to measure drug-response based on a tissue slice culture approach.MethodsTumor tissue slices of hepatic metastases of nine patients suffering from colorectal carcinoma were cultivated for 72 h and treated with different concentrations of the clinically relevant drugs Oxaliplatin, Cetuximab and Pembrolizumab. Easy to use, objective and automated analysis routines based on the Halo platform were developed to measure changes in proliferative activity and the morphometric make-up of the tumor. Apoptotic indices were assessed semiquantitatively.ResultsUntreated tumor tissue slices showed high morphological comparability with the original “in vivo”-tumor, preserving proliferation and stromal-tumor interactions. All but one patients showed a dosage dependent susceptibility to treatment with Oxaliplatin, whereas only two patients showed responses to Cetuximab and Pembrolizumab, respectively. Furthermore, we identified possible non-responders to Cetuximab therapy in absence of RAS-mutations.ConclusionsThis is the first time to demonstrate feasibility of the tissue slice culture approach for metastatic tissue of colorectal carcinoma. An automated readout of proliferation and tumor-morphometry allows for quantification of drug susceptibility. This strongly indicates a potential value of this technique as a patient-specific test-system of targeted therapy in metastatic colorectal cancer. Co-clinical trials are needed to customize for clinical application and to define adequate read-out cut-off values.

Highlights

The lack of predictive biomarkers or test systems contributes to high failure rates of systemic therapy in metastasized colorectal carcinoma, accounting for a still unfavorable prognosis
We describe a protocol for optimal tissue slice culture of hepatic metastases of colorectal carcinoma and propose an automated, easy to use and objective readout strategy for measuring susceptibility to Oxaliplatin, Cetuximab and Pembrolizumab
Tissue slice culture The tumor tissue slice culture technique was adjusted for liver metastases of colorectal cancer patients

Summary

Introduction

The lack of predictive biomarkers or test systems contributes to high failure rates of systemic therapy in metastasized colorectal carcinoma, accounting for a still unfavorable prognosis. We present an ex vivo functional assay to measure drug-response based on a tissue slice culture approach. Martin et al BMC Cancer (2019) 19:1030 irresponsiveness to anti-EGFR antibodies (e.g. Cetuximab) [7,8,9,10] Other factors such as the tumor-stromal interaction; the specific immune landscape and epigenetic factors seem to play a major role in defining its biological behavior that cannot be predicted with molecular profiling alone [11, 12]. A promising technique to overcome this predicament is to measure therapeutic response using an ex vivo functional assay that cultivates a viable sample of the tumor itself. Few research groups have shown that the functional assessment of primary colorectal carcinoma tissue is feasible using this innovative technique [14,15,16]. Stratifying patients with metastatic disease into optimal therapy-regiments requires sampling and cultivation of the metastatic tumor tissue

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