Abstract 2054: Patient relevant preclinical in vivo models using image-guided small animal irradiation for drug discovery

Abstract

Abstract BACKGROUND: Radiotherapy is a primary, adjuvant or neoadjuvant treatment for a number of different cancers such as glioblastoma, breast, lung and prostate. Image-guided radiotherapy (IGRT) is widely used to treat cancer patients providing more accurate treatment plans and reduced side effects. However in the preclinical setting the use of IGRT is less common with traditional irradiation studies utilising whole body irradiation with lead shielding attempting to focus the radiation to specific area on the animal or simple single beam techniques. The development of the image-guided small animal radiation research platform (SARRP) allows the treatment of animal models of cancer more accurately and importantly, with planned protocols similar to those utilised in the clinic. In addition the high precision beam geometry allows the platform to be used in vitro in multi-well assays providing a more high-throughput system for screening. METHODS: We have established multiple cancer models which incorporate bioluminescence to track primary orthotopic and metastatic lesions in real-time using the Spectrum CT imaging system. Tumor growth was monitored longitudinally through quantification of the bioluminescent signal. Bioluminescence from established tumor was correlated to CT and co-registered with the integrated CT on the SARRP platform to allow estimation of tumor dimensions and position in order to deliver a more accurate dose of irradiation specifically to tumors whilst sparing the surrounding normal tissue. In addition we have established Caucasian non-small cell lung cancer (NSCLC) patient-derived xenograft (PDX) models which are admixed with human stroma and evaluated SARRP in these. Tumor specific protocols and dose calculation for irradiation were designed to deliver appropriate irradiation dose to immuno-deficient mice bearing xenografted tumor either alone or in combination with targeted agent or chemotherapeutic. RESULTS: Mice treated with SARRP tolerated irradiation doses in a range of different models either alone or in combination. Validation of different protocols will be reported as well as intrinsic resistant profiles for different models and outcome of any combination treatments to re-sensitize resistant cancer to radiotherapy. CONCLUSIONS: The SARRP platform allows the use of irradiation alone or in combination with anti-cancer agents in small animals with reduced side effects and improved clinical outcome allowing these novel preclinical models to be used effectively for drug discovery programmes to ultimately improve efficacy and treatment options for cancer patients using radiotherapy. Citation Format: Rajendra Kumari, Andrew McKenzie, Nektaria Papadopoulou, Yinfei Yin, Martin Page, Henry Li, Ian Wilson. Patient relevant preclinical in vivo models using image-guided small animal irradiation for drug discovery. [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 2054. doi:10.1158/1538-7445.AM2014-2054