Abstract 4168: Comprehensive characterisation of a newly established patient-derived pancreatic adenocarcinoma xenograft collection

Abstract

Abstract There is a high medical need to identify new treatments for patients with pancreatic cancer, since in many cases only palliative treatment is possible. The standard 1st line chemotherapy in inoperable, locally advanced (stage II and III) and metastatic (stage IV) adenocarcinoma of the pancreas is Gemcitabine as a single agent with a median survival of about 6 month. In addition, Gemcitabine is indicated as adjuvant chemotherapy after surgery. Although the anti-metabolite 5-Flourouracil (5-FU) and the EGF-R inhibitor Tarceva (Erlotinib) have been approved for 2nd line treatment, new and more efficient drugs are urgently needed. In the present study, more than 60 samples of pancreatic carcinomas were transplanted subcutaneously (s.c.) into NMRI nude mice directly after tumor resection. In most cases, tumor material from chemonaive patients with defined histology and staging was used for implantation. Up to now, 17 tumor models were passaged in nude mice and characterized comprehensively. In general, the histology of the primary tumor was comparable to that of the established xenograft. Chemosensitivity in vivo was evaluated by treatment of tumor bearing nude mice with 5-FU (100 or 75mg/kg, q7dx3, i.p.), Gemcitabine (240mg/kg, q7dx3, i.v.) and Erlotinib (25 and 50mg/kg, qdx21, p.o.). In general, tumor growth was not inhibited with best T/C values >50% highlighting the general chemoresistance of pancreatic cancer. Only for two models (PAXF 1872 and PAXF 1998), a high sensitivity towards Gemcitabine was evident with best T/C values of 8% and 3.8%, respectively. There was no correlation to the transcriptional levels of proteins involved in transportation and metabolism of Gemcitabine. Concerning Erlotinib, best T/C values were ranging from 89.6% (PAXF 1876) to 38.5% (PAXF 1982) with no correlation to EGFR expression status. A more broad chemosensitivity profile was established with the ex-vivo clonogenic assay. Interestingly, several tumors responded strongly to treatment with Rapamycin (IC50 ≤ 10nM). Based on this data, in vivo treatment experiments with RAD001 (Everolimus) were done and data are presented. Mutational analysis of p53 (exons 4 to 10) revealed only 4 out of 13 models as p53 wild-type. Nevertheless, the p53 pathway is dysregulated in all tumor models and for selected tumors, an aneuploid cell population was identified by ex vivo cell cycle analysis. In summary, a unique collection of patient-derived pancreatic xenograft models of high clinical relevance has been established. These models are available for translational research studies including in-vivo efficacy testing of new investigational drugs. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 4168.