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Cardiac MRI of small animal models of cancer radiation therapy (RT) is a valuable tool for studying the effect of RT on the heart. However, standard cardiac MRI exams require long scanning times, which is challenging for sick animals that may not survive extended periods of imaging under anesthesia. The purpose of this study is to develop an optimized, fast MRI exam for comprehensive cardiac functional imaging of small-animal models of cancer RT. Ten adult female rats (2 non-irradiated and 8 irradiated) were scanned using the developed exam. Optimal imaging parameters were determined, which minimized scanning time while ensuring measurement accuracy and avoiding imaging artifacts. This optimized, fast MRI exam lasted for 30 min, which was tolerated by all animals. EF was normal in all imaged rats, although it was significantly increased in the irradiated rats, which also showed ventricular hypertrophy. However, myocardial strain was significantly reduced in the irradiated rats. In conclusion, a fast MRI exam has been developed for comprehensive cardiac functional imaging of rats in 30 min, with optimized imaging parameters to ensure accurate measurements and tolerance by irradiated rats. The generated strain measurements provide an early marker of regional cardiac dysfunction before global function is affected.

Over half of all cancer patients receive radiation therapy (RT). However, radiation exposure to the heart can cause cardiotoxicity. Nevertheless, there is a paucity of data on RT-induced cardiac damage, with limited understanding of safe regional RT doses, early detection, prevention and management. A common initial feature of cardiotoxicity is asymptomatic dysfunction, which if left untreated may progress to heart failure. The current paradigm for cardiotoxicity detection and management relies primarily upon assessment of ejection fraction (EF). However, cardiac injury can occur without a clear change in EF.To identify magnetic resonance imaging (MRI) markers of early RT-induced cardiac dysfunction.We investigated the effect of RT on global and regional cardiac function and myocardial T1/T2 values at two timepoints post-RT using cardiac MRI in a rat model of localized cardiac RT. Rats who received image-guided whole-heart radiation of 24Gy were compared to sham-treated rats.The rats maintained normal global cardiac function post-RT. However, a deterioration in strain was particularly notable at 10-weeks post RT, and changes in circumferential strain were larger than changes in radial or longitudinal strain. Compared to sham, circumferential strain changes occurred at the basal, mid-ventricular and apical levels (p0.05 for all at both 8-weeks and 10-weeks post-RT), most of the radial strain changes occurred at the mid-ventricular (p=0.044 at 8-weeks post-RT) and basal (p=0.018 at 10-weeks post-RT) levels, and most of the longitudinal strain changes occurred at the apical (p=0.002 at 8-weeks post-RT) and basal (p=0.035 at 10-weeks post-RT) levels. Regionally, lateral myocardial segments showed the greatest worsening in strain measurements, and histologic changes supported these findings. Despite worsened myocardial strain post-RT, myocardial tissue displacement measures were maintained, or even increased. T1/T2 measurements showed small non-significant changes post-RT compared to values in non-irradiated rats.Our findings suggest MRI regional myocardial strain is a sensitive imaging biomarker for detecting RT-induced subclinical cardiac dysfunction prior to compromise of global cardiac function.

Radiation is a key modality in the treatment of many cancers; however, it can also affect normal tissues adjacent to the tumor, leading to toxic effects. Radiation to the thoracic region, such as that received as part of treatment for breast and lung cancer, can result in incidental dose to the heart, leading to cardiac dysfunction, such as pericarditis, coronary artery disease, ischemic heart disease, conduction defects, and valvular dysfunction. The underlying mechanisms for these morbidities are currently being studied but are not entirely understood. There has been increasing focus on the role of radiation-induced mitochondrial dysfunction and the ensuing impact on various cardiac functions in both preclinical models and in humans. Cardiomyocyte mitochondria are critical to cardiac function, and mitochondria make up a substantial part of a cardiomyocyte's volume. Mitochondrial dysfunction can also alter other cell types in the heart. This review summarizes several factors related to radiation-induced mitochondrial dysfunction in cardiomyocytes and endothelial cells. These factors include mitochondrial DNA mutations, oxidative stress, alterations in various mitochondrial function-related transcription factors, and apoptosis. Through improved understanding of mitochondria-dependent mechanisms of radiation-induced heart dysfunction, potential therapeutic targets can be developed to assist in prevention and treatment of radiation-induced heart damage.

Radiation therapy (RT) is an important component of cancer therapy, with >50% of cancer patients receiving RT. As the number of cancer survivors increases, the short- and long-term side effects of cancer therapy are of growing concern. Side effects of RT for thoracic tumors, notably cardiac and pulmonary toxicities, can cause morbidity and mortality in long-term cancer survivors. An understanding of the biological pathways and mechanisms involved in normal tissue toxicity from RT will improve future cancer treatments by reducing the risk of long-term side effects. Many of these mechanistic studies are performed in animal models of radiation exposure. In this area of research, the use of small animal image-guided RT with treatment planning systems that allow more accurate dose determination has the potential to revolutionize knowledge of clinically relevant tumor and normal tissue radiobiology. However, there are still a number of challenges to overcome to optimize such radiation delivery, including dose verification and calibration, determination of doses received by adjacent normal tissues that can affect outcomes, and motion management and identifying variation in doses due to animal heterogeneity. In addition, recent studies have begun to determine how animal strain and sex affect normal tissue radiation injuries. This review article discusses the known and potential benefits and caveats of newer technologies and methods used for small animal radiation delivery, as well as how the choice of animal models, including variables such as species, strain, and age, can alter the severity of cardiac radiation toxicities and impact their clinical relevance.

Purpose/Objectives: Radiation therapy is used by more than 50% of breast cancer patients, but radiation doses can be limited by normal tissue side effects. For example, breast cancer radiation therapy can improve breast cancer-specific survival, but increase cardiac deaths in those with left-sided cancers. Identifying genetic factors that can enhance tumor radiation sensitivity while decreasing normal tissue toxicities has the potential to improve the therapeutic ratio of radiation therapy – leading to more cures and less long-term toxicities. The use of animal models with differing genetic backgrounds to assess radiation toxicity, followed by genetic mapping of radiosensitivity phenotypes, has the potential to identify new targets that can predict cardiac toxicity from radiation therapy. This project examines how genetic host factors alter normal tissue toxicity risks from breast cancer radiation. Materials/Methods: Inbred female SS rats and SS.BN3 consomic rats, that are genetically identical to SS rats except that chromosome 3 is inherited from the BN strain, have previously been shown to exhibit different vascular dynamics and breast tumor growth. For this study, adult female SS and SS.BN3 rats received image-guided whole heart radiation to a dose of 21 Gy (3 fields, AP and 2 laterals). Cardiac troponin was serially measured at 2, 6, and 12 weeks, and echocardiograms with strain analysis were performed at baseline and 3 months. The Student's t-test was used to compare values. Results: The SS female rats exhibited enhanced cardiac toxicity compared to SS.BN3 rats, with cardiac troponin levels elevated at 12 weeks (0.32 ng/ml vs.0.08 ng/ml for SS vs. SS.BN3, p=0.01), and moderate to severe pericardial effusions seen in 6 of 9 SS rats vs. 2 of 7 SS.BN3 rats. At 3 months post-radiation, echocardiograms revealed increased left ventricular posterior wall thickness at end diastole (LVPWd) in SS vs. SS.BN3 rats (0.25 vs. 0.20 cm, p=0.002) and increased left ventricular mass (LVM) in SS vs. SS.BN3 rats (1.54 vs. 1.28 g, p Conclusions: These results demonstrate that genetic variant on rat chromosome 3 alter the radiosensitivity to single fraction cardiac radiation therapy. Gene expression analysis and genetic mapping will be performed to identify the causative target(s). These models will also be expanded to test whether similar results are seen with fractionated cardiac radiation therapy. This project has the potential to enhance the effectiveness and toxicity profile of radiation therapy in breast cancer. Citation Format: Bergom C, Schlaak R, Frei A, Fish BL, Harmann L, Gasperetti T, Schottstaedt AM, Flister MJ, Medhora M, Strande JL. The use of consomic animal models to identify genetic factors that modulate radiation-induced cardiac toxicity [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-18.

While radiation therapy (RT) can improve cancer outcomes, it can lead to radiation-induced heart dysfunction (RIHD) in patients with thoracic tumors. This study examines the role of adaptive immune cells in RIHD. In Salt-Sensitive (SS) rats, image-guided whole-heart RT increased cardiac T-cell infiltration. We analyzed the functional requirement for these cells in RIHD using a genetic model of T- and B-cell deficiency (interleukin-2 receptor gamma chain knockout (IL2RG&minus, /&minus, )) and observed a complex role for these cells. Surprisingly, while IL2RG deficiency conferred protection from cardiac hypertrophy, it worsened heart function via echocardiogram three months after a large single RT dose, including increased end-systolic volume (ESV) and reduced ejection fraction (EF) and fractional shortening (FS) (p &lt, 0.05). Fractionated RT, however, did not yield similarly increased injury. Our results indicate that T cells are not uniformly required for RIHD in this model, nor do they account for our previously reported differences in cardiac RT sensitivity between SS and SS.BN3 rats. The increasing use of immunotherapies in conjunction with traditional cancer treatments demands better models to study the interactions between immunity and RT for effective therapy. We present a model that reveals complex roles for adaptive immune cells in cardiac injury that vary depending on clinically relevant factors, including RT dose/fractionation, sex, and genetic background.

Background: The tumor microenvironment (TME) is known to impact tumor growth, metastatic potential, and treatment response. Nearly all studies of head and neck cancer (HNC) have focused on somatic mutations in the malignant cells. We hypothesized that genetic determinants limited to the microenvironment would influence HNC growth and metastatic potential. Approach: To demonstrate the impact of genetic differences in the TME on HNC cell line in vivo growth we utilized a novel tool, the consomic xenograft model (CXM). A consomic rat has an entire chromosome substituted into the isogenic background of another inbred strain by selective breeding. Use of immunodeficient (IL2Rγ-/-) consomic rats allows one to study the influence of stromal genetics on tumor biology without the confounding effect of differences in the immune system through the orthotopic implantation of cancer cells into different consomic rat strains. In this system, any differences in tumor growth or metastases are due to differences in the TME rather than cancer cells or immune response. We utilized SS and SS.BN3 consomic rat strains, previously shown to affect the growth of breast tumors, to study the effects of the TME on HNC tumor growth using two well-characterized HPV negative HNC cell lines, SCC-6 (base of tongue derived) and SCC-22b (derived from a hypopharyngeal cancer that had metastasized to lymph nodes). Both cell lines were modified to stably express luciferase. HNC cells were inoculated into the tongue of SS and SS.BN3 animals and tumor growth was monitored by biophotonic imaging after luciferin injection. Results: A significant difference in the tumor growth was seen between rat strains for both cell lines, with the SS.BN3 rats exhibiting less tumor growth and metastasis. Median luciferase activity from baseline increased by 4.1-fold vs. 1.1 fold in SCC-6 tumors in SS vs SS.BN3 rats, respectively (p Conclusions: The use of the CXM model demonstrates an important role for the TME in the growth and metastatic spread of HNC cell lines. This model allows for future congenic mapping to identify the causative genetic variants in the TME mediating the HNC changes in tumor growth and metastasis. Citation Format: Michael W. Straza, Amy Rymaszewski, Kwangok P. Nickel, Anne Frei, Anirban Chatterjee, Rachel Schlaak, Amit Joshi, Michael Flister, Randy J. Kimple, Carmen Bergom. The consomic xenograft model identifies genetic changes in the tumor microenvironment that alter the growth and metastasis of head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5898. doi:10.1158/1538-7445.AM2017-5898