Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery

Abstract

Preclinical models that can accurately predict outcomes in the clinic are much sought after in the field of cancer drug discovery and development. Existing models such as organoids and patient-derived xenografts have many advantages, but they suffer from the drawback of not contextually preserving human tumour architecture. This is a particular problem for the preclinical testing of immunotherapies, as these agents require an intact tumour human-specific microenvironment for them to be effective. In this review, we explore the potential of patient-derived explants (PDEs) for fulfilling this need. PDEs involve the ex vivo culture of fragments of freshly resected human tumours that retain the histological features of original tumours. PDE methodology for anti-cancer drug testing has been in existence for many years, but the platform has not been widely adopted in translational research facilities, despite strong evidence for its clinical predictivity. By modifying PDE endpoint analysis to include the spatial profiling of key biomarkers by using multispectral imaging, we argue that PDEs offer many advantages, including the ability to correlate drug responses with tumour pathology, tumour heterogeneity and changes in the tumour microenvironment. As such, PDEs are a powerful model of choice for cancer drug and biomarker discovery programmes.

Deconvolution of Cell Type-Specific Drug Responses in Human Tumor Tissue with Single-Cell RNA-seq

“…drug response. Acute slice cultures are an attractive approach to modeling drug response in solid tumors because multiple cultures can be rapidly generated from a single surgical specimen, and they do not require extensive culturing or manipulation, which leads to distortion of the native composition of the tissue, selection, and loss of heterogeneity by diluting populations that do not proliferate rapidly [1][2][3] .…”

Phospholipid dynamics in ex vivo lung cancer and normal lung explants

“…Cultured explants or slices derived from human tumors are increasingly being utilized as a tumor model that maintains cell diversity and tissue architecture (for reviews, see refs. 41,42 ). In cancer metabolism studies, this model allows the use of a defined and flexible tracer and the delineation of metabolic activity in the target tissue without systemic influences 20,41 .…”

Ex vivo modelling of drug efficacy in a rare metastatic urachal carcinoma

“…With advanced disease these treatments often fail, and no additional therapeutic options are available due to lack of clinical evidence on targeted treatments. In the future, combination of diagnostic therapy efficacy screening with genomic information [1][2][3][37][38][39][40] could provide a robust diagnostic approach for personalized cancer medicine including immunooncology therapies [41] and thereby shift the clinical practice paradigm also in rare cancers. Currently the ex vivo screening techniques are under intense development and multiple different approaches has been described by different research groups [1][2][3][37][38][39][40][41].…”