Abstract A14: Patient-derived tumor xenografts supporting development of targeted drugs.

Abstract

Abstract Almost in parallel with the new millennium processes in drug development for cancer therapy have changed substantially. Insight in the cancer biology have revealed this disease as a complex genetic disorder leading to a high variety of phenotypes among the different individuals. Many tumors present a very specific pattern of molecular changes and this leads to a heterogenous individual response to drugs. The correct identification of predictive biomarkers selecting the most appropriate therapies and avoiding unnecessary treatments for an individual patient is still a challenge. Patient-derived tumor xenografts allow preclinical investigations in a clinically relevant way. We performed investigations to improve the understanding of cancer complexity and to draw rational conclusions for therapy decisions. Tumor models were established by direct transplantation of surgical specimens to immunodeficient mice and were maintained in early passages. We have shown a high correlation between original patient sample and xenograft both at gene and protein level. We established several large panels of tumor models: i.e. 10 breast, 30 colorectal, 25 lung, 6 ovarian, 10 sarcomas, and 30 leukemias (25 ALL and 5 AML). During the characterization of the xenografts for response towards clinically used anticancer drugs, the analysis for mutations and of gene expression revealed interesting correlations. In NSCLC models upregulation of hypoxia marker genes correlated with resistance to microtubule targeted drugs. In the colon cancer xenografts KRAS mutations predicted resistance to cetuximab. We further identified a potential set of 20 genes which may be predictive for oxaliplatin response. These results demonstrate, that the ability to assess anti-tumor activity in well-characterized xenografts in correlation with particular genetic or molecular characteristics may support the development of new therapeutic regimens. Conclusions from what we discussed are:drug discovery, systems biology, and translational research are moving together to address all the new hallmarks of cancer - increasing the success rate of drug discoverypanels of patient derived xenograft models represent an important tool for translational research to address clinically relevant questions in a standardized and strictly controlled fashionpredictive value of the preclinical models is increasing steadily - they show a high concordance with the clinical specimens concerning marker expression and response to therapy Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A14.