Abstract 3853: Patient-derived xenograft models from peritoneal metastasis of colorectal carcinoma as novel platform for biomarker analysis and drug testing

Colorectal carcinoma (CRC) is associated with high incidence and mortality rate, particularly if metastasized to distant sites, such as the peritoneum. At time of first diagnosis 4 to 7 percent of the patients suffer from peritoneal metastasis (PM) of CRC. The PM is associated with poor prognosis and limited therapeutic options. Therefore, availability of adequate in vivo models for PM will promote the search for novel prognostic or even predictive biomarkers as well as the evaluation of chemosensitivity of PM towards standard, targeted and novel drugs. In this regard such models could be employed for more individualized concepts to improve the therapeutic outcome of PM patients. During the last decade patient-derived xenograft (PDX) mouse models have gained importance, since they closely resemble the molecular and biological features of the original primary tumors. However, until now no PM PDX models have been established from CRC. We therefore focused on the establishment and characterization of a novel CRC PM panel of PDX as useful platform for preclinical studies. For the PDX establishment colorectal surgical specimens were subcutaneously (s.c.) transplanted onto immunocompromized NOD scid gamma (NSG) mice. The successfully engrafted tumors were transferred to NMRI nu/nu mice for further passaging. Engrafted tumors were characterized by histopathology, immunohistochemistry and gene expression analyses using real-time RT-PCR. Chemosensitivity of PDX models was evaluated in vivo by application of a panel of conventional chemotherapeutic and of targeted drugs. For PDX establishment 68 CRC surgical specimens were transplanted onto NSG mice. From those, currently 22 PDX have engrafted and are stably growing on NMRI nu/nu mice. From those, 13 models of 10 patients have been analyzed. Their tumor doubling times ranged between 4 to 28 days. The histopathological evaluation revealed maintenance of the original CRC histology in the PDX. The chemosensitivity testing of conventional and of targeted drugs in the 13 PM PDX models revealed the individual, diverging response of the PDX, such as for 5-FU, irinotecan, oxaliplatin, cetuximab, and erlotinib. For selected PDX, orthotopic transplantation into the peritoneum revealed their potential to form disseminated tumors in kidney, ovaries and abdominal diaphragm. Our results demonstrate, that this novel panel of PDX maintains the morphology of the patient tumor in early passages, reflect heterogeneous response rates,