Brain Cancer @ Leeds

Brain Metastasis Group

Members

Research Overview

Once the cancer has spread from the primary site to distant organs in the body to form metastases, it becomes very difficult to treat. Brain metastases occur in 20-40% of cancer patients and mainly originate from the lung cancer, breast cancer and melanoma. Our goal is to better understand the biology of brain metastases and their interaction with the tumour microenvironment in order to enable the development of more effective therapeutic approaches.

Understanding the cross-talk between macrophages and cancer cells in brain metastases
Macrophages In contrast to primary tumors, the understanding of macrophages in metastases is very limited. Using in vivo models, we investigated the regulation of macrophage phenotypes at two clinically relevant intracranial metastatic sites – brain parenchyma and the dura. We identified significant differences in the activation state of metastasis-associated macrophages (MAMs) at the two locations. Concurrently, cancer cells that have metastasized to the brain parenchyma as compared to the dura differed in the inflammation-related pathways. Lymphotoxin β secreted by cancer cells caused polarization of parenchymal MAMs towards M2 state. This demonstrated that the MAM activation state is codetermined by the metastatic site-specific properties of cancer cells (Oncotarget, 2016)

Harnessing hematopoietic stem cells for the delivery of therapies to brain tumours
Treatment of brain tumours is hampered by the blood-brain barrier that hinders delivery of drugs into the brain. We are exploiting genetically modified hematopoietic stem cells and their progeny, which efficiently home to brain metastases and glioma, for the delivery of immunomodulatory molecules in order to manipulate the tumour microenvironment for therapeutic purpose.

How can we improve the efficacy of immune checkpoint inhibitors in brain metastases?
PD-1 and CTLA-4 are immune-inhibitory receptors (immune checkpoints) expressed mainly on T cells and their inhibition with function-blocking antibodies has been shown to enhance anti-tumor T cell responses. Recently, immune checkpoint inhibition (ICI) with anti-CTLA-4 (Ipilimumab) and anti-PD-1 antibodies (Nivolumab, Pembrolizumab) has revolutionized the treatment of many cancers, including metastatic melanoma. Immune responses in the brain differ from responses elsewhere. Because up to 60% of patients with metastatic melanoma develop brain metastases, it is critical to understand how ICI works in the brain. Towards this goal we are using preclinical in vivo models to define the mechanisms required for ICI efficacy in brain metastases and to identify approaches that could improve therapeutic responses.

Establishing intracranial patient-derived tumour xenografts as improved pre-clinical models
The development of effective therapies requires linking of the information extracted from patient tumour specimens to functional validation. The quality of pre-clinical models used for validation critically impacts clinical success of therapies. In contrast to cell lines, patient-derived tumour xenografts (PDTXs) of primary breast tumours have been shown to closely resemble patient tumours in terms of their molecular profiles and therapeutic responses. Based on this and taking into account tumour microenvironment that critically impacts tumour characteristics, we established and characterized several intracranial brain metastases-derived PDTXs. These models are expected to enable a better prediction of drug efficacy in the brain at the pre-clinical level.

Identifying molecular players involved in breast cancer cell dormancy in the brain
Disseminated cancer cells remain dormant for years before progressing to symptomatic lesions. Dormant cancer cells are also found in the brains of patients at autopsy and in animal models of brain metastasis. We hypothesize that maintaining small lesions in a dormant state or inducing dormancy in established brain lesions is a promising therapeutic strategy to inhibit lethal tumour growth. Towards this goal, we aim to identify molecular targets involved in cancer cell dormancy in the brain that could be exploited for therapeutic purposes.

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