Patient-Derived Xenografts of Non Small Cell Lung Cancer: Resurgence of an Old Model for Investigation of Modern Concepts of Tailored Therapy and Cancer Stem Cells

Abstract

Current chemotherapy regimens have unsatisfactory results in most advanced solid tumors. It is therefore imperative to devise novel therapeutic strategies and to optimize selection of patients, identifying early those who could benefit from available treatments. Mouse models are the most valuable tool for preclinical evaluation of novel therapeutic strategies in cancer and, among them, patient-derived xenografts models (PDX) have made a recent comeback in popularity. These models, obtained by direct implants of tissue fragments in immunocompromised mice, have great potential in drug development studies because they faithfully reproduce the patient's original tumor for both immunohistochemical markers and genetic alterations as well as in terms of response to common therapeutics They also maintain the original tumor heterogeneity, allowing studies of specific cellular subpopulations, including their modulation after drug treatment. Moreover PDXs maintain at least some aspects of the human microenvironment for weeks with the complete substitution with murine stroma occurring only after 2-3 passages in mouse and represent therefore a promising model for studies of tumor-microenvironment interaction. This review summarizes our present knowledge on mouse preclinical cancer models, with a particular attention on patient-derived xenografts of non small cell lung cancer and their relevance for preclinical and biological studies.

Cancer Cell Lines for Drug Discovery and Development

“…Recent studies have suggested that PDX models might hold great promise for testing novel drug candidates as well as to identify rational combination therapies (17). Among the arguments made for PDX models is that they may be expected to provide a better representation of within tumor heterogeneity and also that they would reflect the relevant human components of the tumor microenvironment better (Table 1).…”

“…Several reports also describe the loss of human stromal cells within the first few passages after engraftment (17,21), which raises the question of the possibility of species incompatibility with respect to human tumor-mouse microenvironment interactions. This is emphasized by the results of Hylander and colleagues (22), who showed that by the first passage of PDX tumors, the stroma and vessels supporting their growth are of murine origin (22).…”

Microenvironment-Modulated Metastatic CD133+/CXCR4+/EpCAM− Lung Cancer–Initiating Cells Sustain Tumor Dissemination and Correlate with Poor Prognosis

“…PDX were established from primary lung cancers from patients undergoing surgical resection, who gave their informed consent and expanded as previously described (18).…”

“…18) and clinical samples, we phenotypically characterize and functionally prove the existence of a novel subset of CICs, regulated by the microenvironment, driving lung tumor dissemination and metastasis and we identify CXCR4 signaling as a potential target for novel therapeutic strategies.…”

An Antibody–Drug Conjugate That Targets Tissue Factor Exhibits Potent Therapeutic Activity against a Broad Range of Solid Tumors

“…We addressed the capacity of TF-011-MMAE to inhibit the growth of tumors with heterogeneous target expression using PDX models, which are thought to represent the heterogeneity that exists between human tumors (31)(32)(33). Immunohistochemical (IHC) analysis of xenografted primary human tumor biopsies confirmed heterogeneity of tissue factor expression, and seven PDX models were selected on the basis of variable levels of tissue factor expression.…”