Unraveling new therapeutic avenues for breast cancer brain metastasis

Abstract

Significant clinical improvements in diagnostics and therapeutic strategies have increased the survival of patients with breast cancer. The current challenge in the clinic lies in treating patients with metastatic disease, particularly brain metastases. Patients with brain metastases have dire survivals ranging from 4 to 15 months. This is often due to resistance to current therapeutic options leading to high recurrence rates but also patient symptoms development and detection at later stages of the disease. In this thesis, I used newly developed breast cancer brain metastasis models to improve our understanding of brain metastasis biology. We aimed to understand different aspects of this disease from tumor homeostasis to treatment resistance and proposed potential new clinical therapeutic strategies. We start by reviewing the latest technological advancements in the field of intravital microscopy and how they have been applied to monitor metastatic events. Then, we researched how brain metastases behave in the absence of treatment with intravital microscopy. We showed that epithelial-to-mesenchymal transition drives local invasion of brain metastases. By impeding the migration of these mesenchymal tumor cells through knockdown of ARPC3 we decreased the likelihood of tumor recurrence in mice. These mesenchymal tumor cells when re-injected in the brain of mice were shown to be plastic and capable of forming epithelial tumors. Finally, we confirmed the presence of invading mesenchymal tumor cells in a small cohort of resected human breast cancer brain metastases. Next, we investigated which mechanisms were involved in breast cancer brain metastasis chemoresistance. We observed that our drug-naïve breast cancer brain metastasis models did not respond to chemotherapy due to a process known as vascular mimicry. In these vessel-like structures, tumor cells upregulated a drug-efflux pump known as Breast Cancer Related Protein. Inhibition of the expression or activity of this pump resulted in tumor cells responding to chemotherapy. Following, we studied the effects of a biopsy-like injury in brain tumors. We observed an increase in tumor cell malignance after a biopsy in patients and mice. In mice we showed that these effects were a result of the recruitment of macrophages to the injury site. Blocking macrophage recruitment through CCL2 antibody or administering dexamethasone suppressed the adverse effects of a biopsy-like injury. Subsequently, we strategized a new combinatorial treatment to implement immune-checkpoint inhibition for the treatment of brain metastases. We induced tumor senescence via doxorubicin treatments to modulate the brain microenvironment. Tumor senescence led to the recruitment of cytotoxic T cells which expressed PD1. Immune-checkpoint blockade after doxorubicin treatment resulted in the increase of survival of mice. This strategy gives new insights into implementing immune checkpoint inhibitors to brain metastasis. To conclude, in the last chapter of this thesis I summarized all results while discussing them in light of the current literature and proposed directions for future research.