Abstract
Abstract BACKGROUND: Patient derived xenograft (PDX) models sustain tumour heterogeneity and genetic integrity of the original patient sample when passaged in vivo and are highly predictive of clinical efficacy. As such PDX models are widely used for preclinical efficacy testing of anti-cancer agents Radiotherapy is a primary, adjuvant or neoadjuvant treatment for a number of different cancers including lung, breast and prostate with advances in image-guided micro-irradiation (IGMI) being widely used to treat patients providing reduced side effect and more accurate targeting of the tumour. However the use of IGMI in the preclinical setting is less common with traditional irradiation studies utilising a single beam or whole body irradiation with lead shielding to focus the radiation to a specific area on the animal. Here we report the application of the small animal radiation research platform (SARRP) to preclinical models to demonstrate sensitivity and resistance profiling. METHODS: PDX models were generated from NSCLC samples obtained from untreated patients undergoing surgery implanted and maintained in serial passage subcutaneously in MF-1 nude mice (Harlan UK). Tumour growth was monitored by calliper measurements three times weekly and mice recruited to a study when mean tumour volume was ∼200mm3. For irradiation, mice were anaesthetised and CBCT images were acquired using the small animal research platform (SARRP). The MuriSlice software was used to identify the isocenter of the tumour and fractionated irradiation administered (225 kV peak X-ray beams; dose rate of 2.5 Gy/min) using a multi beam approach in order to spare the surrounding normal tissue. Bodyweight and clinical condition of mice monitored daily. RESULTS: Fractionated irradiation doses were successfully delivered to the tumours over a 2 week period, whilst sparing the surrounding normal tissue using the SARRP. Response to treatment was evaluated by tumour growth inhibition. Models across a panel of Caucasian NSCLC PDX were reported to be either responsive or resistant to treatment which was correlated to the molecular characterisation (RNA sequencing) as well as response to other treatments such as standard of care treatment. CONCLUSIONS: PDX models can be dosed with irradiation using the SARRP platform effectively with reduced side effects, improved safety and used to evaluate combinations with anti-cancer agents to derive irradiation schedules and regimens suitable for testing subsequently in clinical trials. Citation Format: Andrew Mckenzie, Nektaria Papadopoulou, Yinfei Yin, Lucy Page, Jason King, Henry Li, Martin Page, Ian Wilson, Rajendra Kumari. Application of small animal image-guided irradiation to preclinical in vivo models, such as patient-derived xenografts, to inform on combination strategies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1802. doi:10.1158/1538-7445.AM2015-1802
Published Version
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