Abstract 5322: Bioluminescence, fluorescence, and biomarker mediated monitoring of an orthotopic model of colon cancer treated with VX-680
Authors: Graeser Ralph , Esser Norbert , Tsurumi Chizuko , Klotzbuecher Andrea , Niedermann Gabriele , Schaefer-Obododzie Cynthia , Schaechtele Christoph 
Published: June 2012

With 10% of all newly diagnosed cases per year, colon cancer ranks within the top 5 cancer types within the USA, and, with a similar figure of people succumbing to the disease, is a major cause of tumor-related deaths. Primary tumors may often be removed via surgery, but metastatic spread poses considerable difficulties and chemotherapeutic treatments are rarely curative. Novel drugs, and predictive pre-clinical model systems to better mimic human disease are therefore urgently needed.

Although subcutaneously implanted tumor cells have been used for pre-clinical drug testing for decades now, the predictive value of these models has recently become the subject of controversy. Orthotopically implanted cells reflect the human disease much better in that organo-typical tumor stromal interactions are enabled, and tumor cells spread to other sites with distribution patterns reflecting the human disease.

Orthotopical implantation requires sensitive imaging modalities, similar to the patient situation. Bioluminescence imaging (BLI) is a well established modality for pre-clinical models, but is not translatable to the clinic. Recently, fluorescence molecular tomography (FTM) imaging has been shown to offer good sensitivity and tissue penetration, and sensitive probes – that may be used in the clinic – have been developed.

A pre-clinical experiment was performed to compare the growth behaviour of orthotopically implanted, luciferase marked HCT116 wild-type and p53 KO human colon cancer cells and test their sensitivity towards the aurora-inhibitor VX-680. Growth of the tumors, and treatment effects were followed in vivo using BLI, and a final imaging analysis with integrisense, using FMT. The in vivo imaging data were validated with necropsy data, including sensitive luciferase assays to detect metastases in organs.

In vivo BLI suggested that p53 KO tumors grew much more aggressive, giving rise to larger, more fragmented signals than their wild-type counterparts. Imaging using integrisense confirmed the presence of much larger tumor masses in the p53 KO than in the wild-type group. VX-680 slightly reduced the BLI signals from both groups. Necropsy results confirmed the tumor size differences between wild-type and p53 KO tumors, also the VX-680 effect against wild-type tumors (−50%, SD 70%). However, the drug appeared ineffective against p53 KO tumors (+120%, SD 70%). Luciferase assays from potential target organs detected an increased metastasation in p53 KO tumor bearing animals compared to those with wild-type tumors. Interestingly, metastasation of the p53 KO tumors to the spleen was sensitive to VX-680 treatment (−90%, SD 20%). The effect of the drug could also be demonstrated in skin biopsies taken from the mice as a surrogate tissue.

This study represents a ‘high content’, partially translatable mouse model applicable also for the testing of other targeted therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5322. doi:10.1158/1538-7445.AM2011-5322