Patient-Derived Xenograft Models of Non-Small Cell Lung Cancer and Their Potential Utility in Personalized Medicine

Abstract

Traditional preclinical studies of cancer therapeutics have relied on the use of established human cell lines that have been adapted to grow in the laboratory and, therefore, may deviate from the cancer they were meant to represent. With the emphasis of cancer drug development shifting from non-specific cytotoxic agents to rationally designed molecularly targeted therapies or immunotherapy comes the need for better models with predictive value regarding therapeutic activity and response in clinical trials. Recently, the diversity and accessibility of immunodeficient mouse strains has greatly enhanced the production and utility of patient-derived xenograft (PDX) models for many tumor types, including non-small cell lung cancer (NSCLC). Combined with next-generation sequencing, NSCLC PDX mouse models offer an exciting tool for drug development and for studying targeted therapies while utilizing patient samples with the hope of eventually aiding in clinical decision-making. Here, we describe NSCLC PDX mouse models generated by us and others, their ability to reflect the parental tumors’ histomorphological characteristics, as well as the effect of clonal selection and evolution on maintaining genomic integrity in low-passage PDXs compared to the donor tissue. We also raise vital questions regarding the practical utility of PDX and humanized PDX models in predicting patient response to therapy and make recommendations for addressing those questions. Once collaborations and standardized xenotransplantation and data management methods are established, NSCLC PDX mouse models have the potential to be universal and invaluable as a preclinical tool that guides clinical trials and standard therapeutic decisions.

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma

“…Microsatellite analysis corroborated that the PDXs originated from the transplanted material, although minor changes, such as loss of heterozygosity and imbalance could be observed. Other studies described genetic modifications (e.g., gene amplification, gain/loss of mutation) in early passage PDXs in comparison to the patients' samples [26,43], despite a high similarity. Some changes might be occurring de novo, or they might reflect selection of pre-existing subpopulations during transplantation.…”

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

“…We generated a patient-derived xenograft (PDX) tumor bank from de-identified NSCLC patient samples collected by the Rutgers Cancer Institute of New Jersey Biospecimen Repository Service through a non-human subjects protocol approved by the Institutional Review Board of Rutgers University (24). PDX T-042, tested at passages 3 and 4, was derived from a human lung adenocarcinoma and confirmed to be WT for KRAS and BRAF.…”

“…PDX T-042, tested at passages 3 and 4, was derived from a human lung adenocarcinoma and confirmed to be WT for KRAS and BRAF. T-042 retained a TP53 R273L mutation present in the original patient tumor (24). …”

Xenograft and organoid model systems in cancer research

“…This suggests that the PDTX deviates from the original tumour over time (Morgan et al, 2017). In addition, drug metabolism and pharmacokinetics differ between mouse and human, which needs to be taken into account (Morgan et al, 2017).…”

“…For the establishment of more PDTO models, it is of high relevance to find the optimal in vitro growth conditions that enable tumour cells to grow, while keeping as much cellular heterogeneity as possible. Selection pressure occurs in both PDTX and PDTO model systems (Morgan et al, 2017;Pauli et al, 2017). Therefore, combining the strengths of both preclinical model Humanized mice are immunodeficient mice engrafted with human hematopoietic stem cells which give rise to a variety of human blood cell lineages throughout the life of the animal.…”