Radiation Biology

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SU_40_2399 - Consomic Rat Models Identify Genetic Factors that Modulate Radiation-Induced Cardiac Toxicity and Inflammation

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Consomic Rat Models Identify Genetic Factors that Modulate Radiation-Induced Cardiac Toxicity and Inflammation
C. Bergom1, R. A. Schlaak1, A. Frei1, A. M. Schottstaedt2, C. A. Mascari1, B. Fish1, L. Harmann1, T. Gasperetti1, J. L. Strande1, M. Medhora1, and M. J. Flister1; 1Medical College of Wisconsin, Milwaukee, WI, 2Case Western Reserve University, Cleveland, OH

Purpose/Objective(s): Radiation therapy (RT) is used by more than 50% of cancer patients, but RT doses can be limited by normal tissue side effects. RT doses are often constrained so the risk of severe damage to normal tissues is <5-10%, meaning that >90% of patients could have RT dose escalation without unacceptable side effects if predictive biomarkers for tissue toxicity were available. The use of animal models with differing genetic backgrounds to assess RT toxicity, followed by genetic mapping of radiosensitivity phenotypes, has the potential to identify new targets that can predict cardiac toxicity from RT.

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 been shown to exhibit different vascular dynamics and breast tumor growth. For this study, adult male and female SS and SS.BN3 rats received image-guided whole heart RT to a dose of 24 Gy to isocenter (AP and 2 laterals). Cardiac troponin was measured via ELISA and echocardiograms were performed at baseline, 3, and 5 mo. Masson’s trichrome collagen staining and IHC were performed on fixed tissues. The Student’s t-test was used to compare values. Survival curves were analyzed with Kaplan-Meier and log-rank test.

Results: The SS rats exhibited enhanced cardiac toxicity compared to SS.BN3 rats. By 150 days post-RT, 7/13 SS rats died from heart failure, while no SS.BN3 rats died (p<0.05). SS rats had cardiac troponin levels elevated at 3 mo (p=0.01). End diastolic volume and end systolic volume were significantly elevated after RT in male and female SS rats (p<0.01). Systolic function, measured with ejection fraction and fractional shortening, was significantly lower in male and female SS vs SS.BN3 rats at 5 months. Radial and circumferential strain, measures of left ventricular contractility, were significantly worse in SS rats at 3 and 5 months (p<0.01). In females, left ventricular mass was significantly elevated at 3 months in SS rats (1.54 vs 1.28 g, p<0.001), and moderate/large pericardial effusions were present in 6/9 SS compared to 3/7 BN3 rats at 3 months, and 6/6 SS rats compared to 1/7 BN3 rats at 5 months. Similar results were seen in a follow-up study using 9 Gy x 5 fractions of cardiac RT. Interstitial fibrosis was not different between the SS and SS.BN3 rat hearts after RT, but perivascular fibrosis was significantly increased in SS rats (p<0.02). IHC staining revealed significantly more CD68+ cells in the SS vs SS.BN3 hearts at 12 weeks post-RT.

Conclusion: These results demonstrate that genetic variant(s) on rat chromosome 3 alter the sensitivity to high dose cardiac RT. Congenic mapping and gene expression studies are ongoing to identify the causative host factor(s) on rat chromosome 3 causing RT sensitivity and enhanced immune responses. This project has the potential to enhance the effectiveness and toxicity profile of RT.

Author Disclosure: C. Bergom: None. R.A. Schlaak: None. A. Frei: None. A.M. Schottstaedt: None. L. Harmann: None. T. Gasperetti: None.

Carmen Bergom, MD, PhD

Medical College of Wisconsin

Disclosure:
Employment
Medical College of Wisconsin: Assistant Professor: Employee, Resident Physician: Employee

Biography:
Carmen Bergom, M.D., Ph.D., is an Assistant Professor in Radiation Oncology at the Medical College of Wisconsin (MCW). She treats breast cancer patients at the MCW Cancer Center, and she also has a translational research laboratory focusing on using innovative genetic models to improve the therapeutic ratio radiation therapy by identifying targets to enhance tumor radiosensitivity and minimize normal tissue toxicities.

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