Abstract 4953: Establishment and validation of models for metastasis developed from patient xenogragrafts (PDX)
Authors: Hoffmann Jens , Orthmann Andrea , Hoffmann Annika , Zeisig Reiner , Fichtner Iduna 
Published: May 2015

While surgery, chemotherapy and radiation mostly enable a successful treatment of primary tumors, an efficient treatment of metastasis still remains challenging. A prerequisite for the development of new drugs is the availability of relevant tumor models for preclinical testing. In the last years, patient derived xenograft (PDX) models have proven to be more relevant for drug screening and translational research than cell line derived xenograft models. While several experimental models of metastasis are already available (J. Hoffmann, et al., Neuro-Oncology, 2009), it was the aim of our study to extent the panel of validated metastasis models derived from patients. We screened PDX for their ability to metastasize in mice. Metastatic outcome was characterized in dependence of injection route, cell number and mouse strain. Time to develop metastases, number of visible metastases in the lung and liver, as well the rate of human DNA detected in these organs were used as evaluation parameter of metastasis.

Method:Tumors from stably growing PDX (I. Fichtner et al., Clin Cancer Res., 2008) were resected and used to produce a single cell suspension. These cells were injected into different mouse strains by routes indicated below to induce metastasis. At defined time points, or when mice became moribund, mice were sacrificed and inspected for macroscopic metastases. Quantification of early disseminated tumor cells was done by TaqMan PCR (Becker et al., 2002). Normalised CT values (CTnorm = ΔCTnegative control - (ΔCTsample) were used as degree of metastasis.

Results: Eight out of 14 PDX models including lung (2x), colon (2x), breast, melanoma, sarcoma, and pancreatic carcinoma have been shown to develop metastases depending on the mouse strain and injection (i.v., i.p., s.c., or orthotopic) route.

Best results were obtained for melanoma (MEL1956) and lung carcinoma (LU9313). Both models developed strong metastasis in lung and liver with CTnorm values &gt; 14 (lung) and 7.9 (liver), if cells were injected i.v. Lu 9313M cells could also be injected orthotopically causing a high degree of metastasis (CTnorm ∼ 10 after 25 days).

Metastasis of colon carcinoma was less effective when initiated via the intravenous route, but was much better if cells were injected i.p. with CTnorm values above 8. Other model with high metastasis rate were the sarcoma SA10133 (i.v. route, CTnorm values &gt; 7.5) and the pancreatic carcinoma Panc 9617 (s.c. route, CTnorm 4 - 9). Three breast cancer PDX were also investigated, but only MA 4296 developed metastases, derived from orthotopically implanted tumor cells with a CTnorm of ∼ 9.8 for the lung.

Outlook: EPO GmbH established a panel of eight different tumor models from PDX to induce metastasis, each with specific conditions. The results of this study may contribute to improve the treatment of cancer by providing models with high clinic relevance for the testing of novel antimetastatic treatments.

Citation Format: Jens Hoffmann, Andrea Orthmann, Annika Hoffmann, Reiner Zeisig, Iduna Fichtner. Establishment and validation of models for metastasis developed from patient xenogragrafts (PDX). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4953. doi:10.1158/1538-7445.AM2014-4953