Val Brunton: Cancer Therapeutics
Imaging of cancer cell phenotypes and drug responses
We are developing and using mouse models of cancer (breast, glioma, sarcoma) to study the role of key adhesion linked proteins in tumour cell progression. Our work combining the use of optical imaging window technology and specific fluorescence-based probes and label-free imaging approaches has enabled us to carry out studies where we can monitor the interaction of tumour cells within the surrounding microenvironment (eg immune infiltrate, extracellular matrix) and also quantify the effects of drugs on tumour cell phenotypes including migration, angiogenesis, apoptosis and protease activation. This allows us to dissect mechanisms of drug activity and provides a robust platform for evaluating new drug therapies. In addition, we are developing label-free Raman technologies to monitor drug uptake and distribution. This is a collaboration between chemists, engineers and optical physicists and is centered around use of our bespoke Raman/2-photon microscope.
Exploiting adhesion networks in glioblastoma
There is a pressing need for improvements in biological understanding and treatment of glioblastoma, whose prognosis remains dismal. Although whole genome sequencing has revealed the complexity of the mutational landscape, it has not yet resulted in new approaches and changes to clinical treatment. We are using new glioblastoma cellular models, including from mice and fresh patient-derived tumour specimens that provide genetically tractable and disease-relevant models that retain key aspects of disease biology. The work aims to exploit glioma cell vulnerabilities by disrupting core adhesion proteins and cancer-specific adhesion complexes. We are combining proteomics, transcriptomics and assessment of biological phenotypes (including use of orthotopic mouse models) with translational studies to develop hypotheses for new treatment strategies in glioblastoma.
Role of Kindlins in tumour cell biology and Kindler Syndrome
Kindlins (Kindlin-1, -2 and -3) are FERM domain containing adaptor proteins whose primary role is thought to be in the activation of integrins and they therefore play a key role in cell-matrix adhesion signalling. Their mis-regulation is associated with a number of diseases including Kindler Syndrome (Kin-1), Leukocyte Adhesion Deficiency type III (Kindlin-3) and cancer (Kindlin-1, -2 and -3). Kindler Syndrome is a skin disorder characterised by skin fragility and blistering and we are using both in vitro and in vivo approaches to study the role of Kindlin-1 in the development Kindler Syndrome and have recently identified a novel role for Kindlin-1 in regulating mitotic spindle orientation within the epidermis (Patel et al., 2013, Nat Commun; Patel et al., 2016 J Mol Cell Biol). We are also studying the role of Kindlin-1 and -2 in cancer development and progression. Our recent work had identified a role for Kindlin-1 in driving pulmonary metastatic colonization through regulation of the tumour microenvironment (Sarvi et al., 2018 Cancer Res).
Understanding the role of the tumour microenvironment in lobular breast cancer
Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer after invasive ductal carcinoma (IDC), which account for 10-15% and 80% of breast cancers respectively. ILC is recognized to exhibit a number of clinico-pathologic characteristics distinct from those of IDC. For example, ILC has an unusual pattern of metastatic dissemination having a predilection for spread to the gastro-intestinal tract, peritoneum and ovary. Despite the originally favorable survival, patients with lobular histology have a worse survival in multivariate analysis after a prolonged follow-up which is in part due to extended periods of metastatic dormancy and a lack of response to chemotherapy.
We have carried out transcriptomic analysis of a series of laser capture microdissected human ILC samples and identified a gene signature that is specific to the tumour microenvironment of ILC. Using mouse models and primary patient derived samples (patient-derived xenografts, organoids) we are looking at how the tumour microenvironment is driving the unique features of ILC.
Generating new sarcoma models
Soft tissue sarcomas are a group of rare cancers for which surgery is the standard treatment for localised disease. Despite optimal management of localised disease, ~50% of patients develop local and distant metastatic relapse leading to poor outcomes. Progress in improving survival in soft tissue sarcoma over the last two decades has been disappointing. Consequently, there is a huge unmet need not only for the improved use of currently available systemic therapies to prevent disease relapse and metastasis but also a better understanding of the underlying biology of these tumours, leading to the rational evaluation and introduction of novel treatments. As part of a European wide consortium we are developing preclinical patient-derived and immune competent mouse models that reflect the human disease to address this unmet need. We are using a using a phenotypic-led screening approach to identify small molecules with potent activity in our sarcoma models to help drive important new target and drug discoveries for the treatment of soft tissue sarcoma.