Preclinical models are crucial in understanding tumor biology. Our team developed various platforms of preclinical models to facilitate drug sensitivity test, drug delivery, N-of-1 trial, identifying novel biomarkers, and new drug discovery.
A patient-derived xenograft (PDX) model is an in vivo animal model which provides biological and genomic profiles similar to a primary tumor. The characterization of factors that influence the establishment of PDX is crucial. Furthermore, PDX models can provide a platform for chemosensitivity tests to evaluate the effectiveness of a target agent before applying it in clinical trials.
We implanted 83 cases of breast cancer into NOD.Cg-Prkdcscid Il2rgtm1Sug/Jic mice, to develop PDX models. Clinicopathological factors of primary tumors were reviewed to identify the factors affecting engraftment success rates. After the establishment of PDX models, we performed olaparib and carboplatin chemosensitivity tests. We used PDX models from triple-negative breast cancer (TNBC) with neoadjuvant chemotherapy and/or germline BRCA1 mutations in chemosensitivity tests. Our basic study using PDX models was published in the literature. [ 1 ]
Collaboration with B.I. (bioinformatics) laboratory
NGS(next generation sequencing) is to evaluate genomic diversification. We are perfoming deep analysis of patient-derived xenograft model from a patient with a germline pathogenic BRCA1 mutation, c.5339T->C; p.Leu1780Pro; rs80357474 (L1780P), that is known as a specific mutation in Korean patients with hereditary breast cancer.
Scheme of establishment of PDX models
Primary cancer cell culture
Primary cancer cell was derived from successful PDX model. Two primary cell lines were successfully obtained from PDX tumor which has BRCA1 L1780P mutation. We confirmed that human cancer cells have been successfully derived from PDX tumor. It is possible to in vitro drug screening using this in vitro models and reliable drug strategies will be tested in these cell lines as well.
Organoids have been derived from successful PDX model. The major difference between primary cell and organoids is a process of culture methods. 3D culture is used for organoids culture. It has been considered that 3D culture well reflected to the complexity of micro environment rather than 2D culture. However, depletion of mouse cells is crucial because organoids are derived from PDX model. After depletion of mouse cells in organoids, it is used for in vitro/in vivo research.
1. Park, H.S., et al., Establishment of chemosensitivity tests in triple-negative and BRCA-mutated breast cancer patient-derived xenograft models. PLoS One, 2019. 14(12): p. e0225082.