Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Abstract

Purpose: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models.Experimental Design: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis.Results: This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance.Conclusions: This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients.

Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer

“…KRAS mutations are well-established predictors of clinical resistance to anti-EGFR treatment in metastatic colorectal cancer ( 4 , 22 ), although this association is not strong in preclinical models (23)(24)(25). Our initial clinical development program focused on metastatic colorectal cancer with wild-type KRAS (determined on archived tumor samples), anticipating that Sym004 could overcome an acquired nongenetic mechanism of resistance to anti-EGFR treatment, even though we did see some activity of Sym004 in colorectal cancer cell lines with mutated KRAS in the presence of ligands.…”

Patient-Derived-Tumor-Xenograft: modeling cancer for basic and translational cancer research

“…Interestingly, these changes could not be reverted once the in vitro propagated cells were re-implanted into mice. Instead, PDTX retain the original tumor heterogeneity, thus allowing for clonal dynamic studies [6,25,30,[42][43][44][45][46]. Moreover, Eirew et al used deep genome and single cell sequencing methods to demonstrate an ongoing clonal selection in both primary and metastatic breast tumors, with the expansion of clones sharing recurrent patterns.…”

Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

“…First, patient-derived xenograft (PDX) tumor models are increasingly feasible and available. [26][27][28][29] Second, evidence is amassing that supports the cancer stem cell (CSC) paradigm: a theoretical model for cancer that accounts for the importance of specific tumor cell subpopulations to a tumor's growth and potential for driving tumor recurrence (reviewed in previous studies [30][31][32] ). Finally, next-generation DNA and RNA sequencing efforts (eg, The Cancer Genome Atlas) have demonstrated that very few common mutations unite particular solid tumor types; rather, patient tumors have a spectrum of mutations that collectively drive tumor growth.…”

“…26,27,[55][56][57] As a natural extension of standard tissue culture techniques, some researchers have taken to the xenotransplantation of traditional tumor cell lines that have been passaged extensively in vitro. These models have empowered remarkable advances in the understanding of angiogenesis and tumor cell invasion, resulting in the development of therapeutic agents such as bevacizumab and sorafenib; 58,59 however, promising preclinical data obtained using these traditional cell line-initiated xenografts has not translated into dramatic improvements in overall survival in most cancer patients.…”