Our Research

Human cancers harbour defects in processes that inhibit or enhance tumour growth, so-called tumour suppressor and oncogenes. Importantly, these abnormalities render the tumour cells resistant to many therapies.

Our research is focused on understanding how cancers develop and finding new therapy approaches, including targeted drugs as well as immune therapies to treat these cancers.

We aim to identify novel genes involved in the development of normal and malignant haematopoiesis. We are using in vivo CRISPR approaches to systematically identify new candidate genes, with the ultimate goal of using these targets as novel anti-cancer therapies.

We have recently also started to understand the mechanisms of therapy resistance in cancers and how we can overcome this by reducing the fitness of the cancer cells or enhancing immune therapies using different CRISPR approaches.

Identification of tumour immune evasion mechanisms

Cancer immune evasion is a major hurdle in for the success of current immunotherapies, both in the context of adoptive cellular therapy (ACT) and immune checkpoint blockade. Despite the clinical success of diverse immunotherapies, many patients do not respond or ultimately relapse, likely due to tumours evolving to escape sufficient recognition by the immune system. Although considerable progress has been made in understanding how cancers evade immunity, measures to counteract tumour immune escape are lacking. We employ cutting-edge screening mechanisms to identify tumour immune evasion mechanisms and avenues to sensitise tumour cells to T cell-mediated killing.

Genetic/epigenetic control of effective anti-tumour T cell responses

Despite the success of adoptive cellular therapy (ACT) in the context of haematological malignancies, response rates against solid malignancies are poor, likely due to tumour-associated immunosuppression and subsequent T cell exhaustion. Indeed, it is becoming clear that the failure of T cells to elicit a successful and long-term anti-tumour immune response is controlled by transcriptional, epigenetic and post-translational modifications. However, our current understanding of the molecules involved in these processes is limited. We use cutting-edge technology including in vitro and in vivo CRISPR screens, high throughput drug screens and novel single cell sequencing protocols to identify novel underlying molecular mechanisms leading to T cell dysfunction in cancer and identify mechanisms to improve T cell function in this context. We employ a variety of pre-clinical models of CAR T cell therapy and re-directed TCR T cell therapy to validate novel immunotherapy targets for translation into the clinic.

Identification of novel immunotherapy approaches.

High-throughput screening has been a staple in drug discovery in recent decades. Target-based drug discovery relies heavily on singular readouts such as reporter gene expression or perturbation of enzymatic activity in response to small molecule treatment. However, with a recent renewed focus on phenotypic based drug discovery, there is an increased interest in more comprehensive and less biased screening methods that combine aspects of both target-based and phenotypic screening, such as RNA-seq. To complement our genetic screens, we also perform high-throughput drug screens for agents that promote favourable states of T cell differentiation for anti-tumour immunity and agents that increase the immunogenicity of cancer cells. Importantly, identification of such agents would allow us to enhance current immunotherapy approaches.

Tumour infiltrating regulatory T cells

Our body’s immune system can recognise and effectively eliminate tumours. To escape immune attack, tumours hijack a specialised immune cell population known as regulatory T cells (Tregs), which potently suppresses anti-tumour immune cells to promote tumour growth. Targeting Tregs, therefore, is an attractive strategy to revert immune suppression in tumours and boost the function of anti-tumour immune cells. Our laboratory aims to discover transcriptional and epigenetic mechanisms employed by Tregs to infiltrate tumours in vital organs such as the gut, lung, liver and brain. These mechanisms will be harnessed to target Tregs for the treatment of solid tumours.

Stromal-immune cell crosstalk

Tumour microenvironment is composed of actively proliferating tumour cells, stromal cells, blood vessels and a plethora of immune cells. Stromal cells are known to produce a variety of growth factors and immunomodulatory molecules that directly shapes the immune landscape of tumours. We use cutting-edge molecular tools and microscopy to understand the molecular makeup of stromal cells in diverse tissues and tumours as well as their crosstalk with immune cells, in particular Tregs.

Metabolic regulation of tumour immunity

Cellular metabolism is critical for the differentiation, growth and function of tumour cells and immune cells. Metabolic intermediates serve as catalysts for several cellular processes including gene transcription. Systemic metabolic changes also influence anti-tumour immune responses and immunotherapy outcomes. Our laboratory aims to understand how cellular metabolism and tumour derived ‘oncometabolites’ shape the transcriptional landscape of tumour infiltrating immune cells. We also investigate how changes in systemic metabolism affects anti-tumour immunity and immunotherapy outcomes.

Eph receptors

Eph receptors are cell surface proteins that guide cell migration by binding to other cell-bound proteins (ephrins) on adjacent cells, thereby controlling cell-cell adhesion. Ephs coordinate cell movement during normal development of tissue and organ boundaries, and the vascular and neural networks. They are generally scarce in adults but reappear in cancers, where they are often on early ‘progenitor’ cell types, associated with blood vessel formation, and tumour cell invasion and spread.

EphA3 is a particular focus, which we investigate in tumour models, using ‘knock-down’ mice or by treatment with a specific antibody we helped develop, with the aid of drug payloads to specifically target the tumour microenvironment.

ADAM metalloproteases

ADAM metalloproteases (or ADAMs) are cell membrane-bound proteases that shed a range of other membrane proteins, regulating the activity of diverse cell surface receptors. These include Ephs and other receptors controlling cancer cell growth, drug resistance, and invasion and spread to other tissues. ADAMs also play an important role in the tumour microenvironment and in inflammation.

ADAM10 and 17 are of particular interest and we are investigating their function in tumours, as well as developing antibodies and antibody-drug conjugates as potential new therapies.

Targeting Strategies in Cancer

We have identified a series of molecules selectively expressed on cancer cells, and in the tumour microenvironment, that can be targeted for cancer therapy. This includes conformationally exposed receptor epitopes, such as found on the Epidermal Growth Factor Receptor (EGFR) and which led to the development of mAb806 and our first-in-human trials of this molecule. Our research findings have provided a new paradigm in antibody-based targeting and therapy of solid tumours. This work has expanded to incorporate structure-function studies of additional novel antibodies we have developed that target cell surface receptors and tumour microenvironment in tumours, as well as investigating mechanisms of resistance to antibody therapeutics, and targeting key molecules involved in sustaining the tumour microenvironment.

Antibody Engineering

We have developed techniques for generation and humanisation of antibodies. Recent molecular engineering, structural and modelling approaches in our laboratory have defined novel Fc:FcRn and Fc:FcγR interactions, which result in improved immune effector function and bioavailability of humanised antibodies. We have also developed strategies to deliver payloads specifically to tumours through conjugation of drugs, toxins and isotopes to recombinant antibodies, peptides and nanoparticles, both in preclinical models and more recently in clinical trials in cancer patients. These studies are showing encouraging results in patients with cancers of the brain, colon and breast, as well as other solid tumours.

Tumour Payload Delivery

The development of recombinant antibodies for cancer therapy has emerged as one of the most promising areas in oncology therapeutics, both as single agents, and for payload delivery. The concept of being able to deliver toxins through antibody-drug conjugates, or radiotherapy by antibody-radioisotope conjugates targeting the payload to sites of disease, are exciting and promising approaches that we are exploring preclinically and clinically with antibodies developed in our laboratory.

Novel Metabolic Tracers

An exciting recent development in the molecular imaging of cancer comes from the identification of critical biochemical pathways responsible for tumour growth and metastasis, and immune targets which can be exploited for therapy, which can be imaged with novel SPECT and positron emission tomography (PET) tracers. Taking the discovery of novel metabolic tracers in the laboratory to clinical trials is a major focus of our molecular imaging / PET research program and is leading to a deeper understanding of tumour biology and therapy response.