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.

Absorbed doses in micro-CT were found to be relatively high. In micro-SPECT∕CT imaging, the micro-CT unit is mainly used to produce a localization frame. As a result, users should pay attention to adjustable CT parameters so as to minimize the radiation dose and avoid any adverse radiation effects which may interfere with biological parameters studied.

Well characterized models representing the heterogeneity of human colorectal cancers (CRC) are needed to develop effective therapeutic agents. Establishment of such tools will allow a better prediction of the clinical outcome, taking into account the diversity of each patient tumor phenotype and genotype. For this purpose and with the financial support of the French Ministry of Industry, we have associated efforts from hospitals, academic groups, biotech and pharmaceutical companies. From May 2007 to January 2009, 86 surgical specimens [59 primary (P) tumors, 19 metastasis (M), and 8 peritoneal carcinomatosis (C)] were collected from CRC patients (with informed consents and negative HBV, HCV, and HIVs serologies). Tumor samples were subcutaneously xenografted in nude mice. The take rate was 57% (P), 55% (C), and 82% (M) with a difference in the take rate between tumor stages (p= 0.0184). We further engrafted in nude mice, SCID mice and nude rats. No significant difference in the take rate and growth was observed between the 2 mouse strains. Most of the mouse-growing tumors (95%) were successfully engrafted in nude rats, however their growth was significantly slower showing a more pronounced stromal component when compared with mice. Characteristics of our models are in accordance with the CRC clinical heterogeneity. Sequence analysis of 54 models has been performed and mutations were observed for KRAS (46%), APC (44%), TP53 (59%), BRAF (11%), PI3KCA (11%), FBXW7 (6%), CTNNB1 (2%), EGFR (2%), and 5/21 present a MSI status. Besides molecular markers, we compared the gene copy number using CGH technology before and after engraftment. The results exhibit high similarity between early passages of xenografts and the original clinical tumor samples. The histological structure and molecular profile were preserved, indicating the relevance of these models. Nevertheless the quality control is required to follow potential molecular deviation after multiple in vivo passages. The established models are being evaluated for ex vivo and in vivo sensitivities to colon anticancer drugs (5-FU, oxaliplatin, irinotecan and cetuximab). In vivo studies performed in our panel show 14/19 models sensitive to 5-FU, 1/19 to oxaliplatin, 7/8 to irinotecan, and 6/19 to cetuximab. We will present the correlation between pharmacological studies, molecular profile and patient clinical history. Preclinical studies on patient-derived tumor models will bring benefits to evaluate novel targeted therapeutic strategies and potentially help the stratification strategy for cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4169.

<p>PDF file, 241K, Frequency of abnormalities detected by aCGH among all samples tested across the genome.</p>

CCR Translation for This Article from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer