ABSTRACT
BACKGROUND: Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease. METHODS: Here we report the development, testing, and validation of a platform to immobilize and target tumors in mice with stereotactic ablative RT (SART). Xenograft and autochthonous tumor models were treated with hypofractionated ablative doses of radiotherapy. RESULTS: We demonstrate that hypofractionated regimens used in clinical practice can be effectively delivered in mouse models. SART alters tumor stroma and the immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. Complete pathologic responses were achieved in xenograft models, but not in GEMMs. CONCLUSIONS: While SART is capable of fully ablating xenografts, it is unable to completely eradicate disease in GEMMs, arguing that resistance to potentially curative therapy can be modeled in GEMMs.
Mice can be used to model the types of cancer seen in people to investigate the effects of cancer therapies, such as radiation. Here, we apply radiation therapy treatments that are able to cure cancer in humans to mice that have cancer of the prostate or colorectum. We show that the mice do not experience many side effects and that the tumours reduce in size, but in some cases show progression after treatment. Our study demonstrates that mice can be used to better understand how human cancers respond to radiation treatment, which can lead to the development of improved treatments and treatment schedules.
ABSTRACT
To ensure reliability and reproducibility of radiobiological data, it is necessary to standardize dosimetry practices across all research institutions. The photoelectric effect predominates over other interactions at low energy and in high atomic number materials such as bone, which can lead to increased dose deposition in soft tissue adjacent to mineral bone due to secondary radiation particles. This may produce radiation effects that deviate from higher energy photon irradiation that best model exposure from clinical radiotherapy or nuclear incidences. Past theoretical considerations have indicated that this process should affect radiation exposure of neighboring bone marrow (BM) and account for reported differences in relative biological effectiveness (RBE) for hematopoietic failure in rodents. The studies described herein definitively estimate spatial dose distribution and biological effectiveness within the BM compartment for (137)Cs gamma rays and 320 kVp X rays at two levels of filtration: 1 and 4 mm Cu half-value layer (HVL). In these studies, we performed: 1. Monte Carlo simulations on a 5 µm resolution model of mouse vertebrae and femur derived from micro-CT images; 2. In vitro biological experiments irradiating BM cells plated directly on the surface of a bone-equivalent material (BEM); and 3. An in vivo study on BM cell survival in irradiated live mice. Simulation results showed that the relative dose increased in proximity to bone at the lower radiation energies and produced averaged values of relative dose over the entire BM volume within imaged trabecular bone of 1.17, 1.08 and 1.01 for beam qualities of 1 mm Cu HVL, 4 mm Cu HVL and (137)Cs, respectively. In accordance with Monte Carlo simulations, in vitro irradiation of BM cells located on BEM and in vivo whole-body irradiation at a prescribed dose to soft tissue of 6 Gy produced relative cell killing of hematopoietic progenitors (CFU-C) that significantly increased for the 1 mm Cu HVL X rays compared to radiation exposures of higher photon energies. Thus, we propose that X rays of the highest possible kVp and filtration be used to investigate radiation effects on the hematopoietic system, as this will allow for better comparisons with high-energy photon exposures applied in radiotherapy or as anticipated in a nuclear event.