Abstract 2698: In vivo imaging of human pancreatic tumor and melanoma models in NOD/SCID mice: Preclinical evaluation of metastases and inhibition by anti-DLL4 treatment
Authors: Beviglia Lucia , Yeung Pete , Miller Steven C. , O'Young Gilbert , Wang Min , Fischer Marcus , Yen Wang-Ching , Lewicki John , Gurney Austin , Hoey Tim , Kapoun Ann M. 
Published: June 2012

Pre-existing metastases at the time of diagnosis are often the cause of death in patients suffering from a number of malignancies, including pancreatic cancer and melanoma. Successful development of effective anti-metastatic cancer therapies requires preclinical metastasis models that mimic the clinical condition of human cancer, sensitive methods of metastasis detection in mice bearing orthotopic tumors, and real-time evaluation of anti-metastatic activity of novel treatments. We have developed orthotopic tumor models in NOD/SCID mice utilizing pancreatic and melanoma tumor cells that are derived directly from human cancer patient specimens. These tumors retain much of the original human cancer heterogeneity, phenotype, and the ability to form metastases in the lungs, liver, intestines, and brain _ recapitulating the metastatic invasiveness seen in the clinic. Since the ability of optical imaging methods to detect tumors and metastases in deep tissues is limited by tumor size and light penetration depth, we employed Zymera's Bioluminescence Resonance Energy Transfer-Quantum Dot (BRET-Qdot®) nanoprobes conjugated with streptavidin ([BRET-Qdot]-SA) to improve sensitivity for detection of both early stage primary tumors and small metastases. The cell surface proteins, MCAM in melanoma and EpCAM in pancreatic tumors, were targeted with human specific biotinylated anti-MCAM or -EpCAM antibodies, (respectively) delivered intravenously or intraperitoneally into NOD/SCID mice and detected with the [BRET-Qdot®]-SA nanoprobe. Light emission from the tumor-bound [BRET-Qdot®]-SA was activated by the catalytic conversion of the luciferase substrate coelenterazine. The novel and highly sensitive BRET-Qdot® technology emits 655 nm bioluminescence light for in vivo imaging of deep tissues. This technology allowed the growth of primary tumors and metastases to be measured overtime in the same mice. Moreover, in efficacy studies we have treated the mice with antibodies developed against the human and the murine DLL4 to target both tumor cells and vasculature that cooperate for the formation and growth of primary tumor and metastases. Treatment with anti-DLL4 inhibits metastases in the lungs, liver, intestine and brain. Finally, we have developed a more clinically relevant melanoma metastasis model consisting of the surgical excision of the primary tumor. This model, characterized by an enrichment of aggressive growth of metastases in the lungs, has been also utilized to evaluate the inhibitory activity of anti-DLL4 antibodies.

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 2698. doi:10.1158/1538-7445.AM2011-2698