Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Dr. Paula Foster

Abstract

Introduction: The incidence of brain metastasis due to breast cancer is increasing and prognosis is poor. Treatment is challenging for this disease because systemic therapy has limited efficacy due to the presence of the blood-brain barrier. In addition, it is thought that disseminated dormant cancer cells persist in metastatic organs and may evade treatment, thereby facilitating a mechanism for later recurrence. Methods: In this thesis, we use contrast-enhanced MRI and high resolution anatomical MRI to characterize blood-brain barrier integrity associated with the development of brain metastases due to HER2+ breast cancer in the SUM-190-BR3, JIMT-1-BR3, and MDA-MB-231-BR-HER2 experimental models. We further use these imaging techniques along with novel micro-irradiation technology to investigate the impact of whole brain radiotherapy on the growth and blood-brain barrier permeability of brain metastases in the MDA-MB-231-BR-HER2 model. Finally, we employed MRI cell tracking to study the fate of proliferative and non-proliferative cancer cells after early radiotherapy. Histology and immunohistochemistry was performed on brain sections corresponding to MRI to validate and further investigate radiological findings. Results: Herein, we show substantial heterogeneity in tumor permeability across three models of brain metastasis due to HER2+ breast cancer. We also demonstrate that whole brain radiotherapy following diagnosis of brain metastasis can mitigate, but not eliminate, tumor growth in the MDA-MB-231-BR-HER2 model. Furthermore, radiotherapy did not impact blood-brain barrier permeability associated with metastases. In comparison, early WBRT was used successfully as a preventative treatment against brain metastatic growth. Still, cellular MRI revealed the persistence of non-proliferative cancer cells in the brain regardless of treatment time point or efficacy against metastasis. Conclusions: Consideration of tumor permeability in brain metastasis models is important when investigating novel therapeutics as blood-brain barrier integrity varies substantially across models of the same disease. Radiotherapy did not increase tumor permeability; however, other strategies should be investigated. Whole brain radiotherapy is effective as a preventative treatment against brain metastasis, but is not curative when delivered after MRI-detectable tumors have developed. The persistence of iron-retaining non-proliferative cancer cells after prophylactic radiotherapy suggests these dormant cells may be able to evade treatment and later could contribute to cancer recurrence.


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