Labs

Epigenetic Therapy

We have found that a group of enzymes called histone deacetylases (HDACs) are required for colon cancer cell growth. We have also found that drugs which block these enzymes induce the differentiation and death of colon cancer cells. We are currently working on ways to further improve the anti-tumour activity of these drugs by combining them with existing therapies, in order to develop a new treatment for colon cancer patients.

Differentiation Therapy

Our laboratory also investigates the transcriptional mechanisms by which cellular and tissue differentiation is disturbed during colorectal tumorigenesis. We have identified a number of key transcription factors which are deregulated during this process, and we are using this information to investigate ways differentiation can be reprogrammed in tumour cells.

Discovery of biomarkers to targeted therapies

Through access to clinical trial samples provided by our long-term collaborator A/Prof Niall Tebbutt, our laboratory has a translational research program aimed at discovering the biomarkers predictive response to targeted therapies in gastrointestinal cancers. Agents we are investigating include anti-angiogenic therapeutics (avastin), EGFR inhibitors (cetuximab), BRAF inhibitors and mTOR inhibitors, in the treatment of colorectal cancer, gastric cancer and cholangiocarcinoma.

Function of intestinal immune cells in bowel cancer

Intraepithelial lymphocytes (IELs) are immune cells which continually survey intestinal epithelial cells for infection or damage. Bowel cancer forms when the epithelial cells become damaged and change, growing in an uncontrolled manner. The role of IELs in this process, and whether or not they play a role in tumour cell growth or killing tumour cells, has not been studied in detail. Our laboratory aims to understand these cells, including the molecules that regulate their function in steady state development and in the development of cancer. 

Regulation of cytokines in the gastrointestinal tract

Cytokines, such as IL-17 and IL-22, are secreted by immune cells and are critical in boosting epithelial cell and tumour survival in the intestine. Bowel cancer patients with increased IL-17 and IL-22 levels experience increased tumour growth and have a poorer prognosis. We are dissecting the molecular pathways and cell types involved in regulating IL-17 and IL-22 production to investigate the role these cytokines play in bowel cancer progression. It is crucial that we understand these mechanisms so we can develop new immune cell-mediated therapies to treat gastrointestinal cancers.

Influence of the microbiome on immune health  

Each person’s microbiome is unique and is made up of good bacteria, viruses and fungi which live on the body’s surfaces, such as the skin and intestine. Our understanding of these resident microbes and how they affect the body’s immune response to an infectious organism or disease, such as cancer, is limited. We are working to understand the mechanisms which link the microbiome to overall immune cell health, including the activation of transcription factors that guide immune cell development, as well as the cytokines they secrete in order to communicate with the rest of the body’s cells.

We constantly use and develop cutting-edge methodologies, including multiplex immuno-fluorescence and RNA-Scope for the characterisation of the tumour microenvironment, protein arrays for the detection of cancer-specific antibodies, and in vitro T cell assays for the detection of novel immunogenic peptides, among others. We are exploring how a successful immune recognition is orchestrated and translated from the early (innate arm) to the late (adaptive) response.

This ‘immunostaging’ of cancers will allow us to understand why and how immunotherapy works for some patients but not for others, and how we can increase the number of patients who benefit from these treatments. The laboratory has extensive experience in clinical trial monitoring and collaborative industry projects, all centred on improving outcomes and quality of life for cancer patients. We collaborate with several leading cancer research laboratories in Australia and internationally.

We focus our research on three approaches to interfere with the communication between cancer and normal cells within a tumour.

Stat3 and tumourigenesis

Pronounced epithelial Stat3 activity is not only observed during wound-healing, but also in a majority of cancers including those in the colon, stomach, breast and lung. Our lab recently established a novel link, showing that the cytokine interleukin (IL)-11 – through its shared gp130 receptor, the associated Jak kinases and Stat3 signaling – promotes tumourigenesis. Surprisingly, this signaling cascade also becomes rate limiting for the growth of colon and gastric tumours that are driven by mutations in well recognised cancer pathways.

Neoplastic cells

We are therapeutically exploiting that neoplastic cells have often developed a higher dependency on a particular signal than their normal counterparts. For instance, oncogenic activation of the WNT/beta-catenin signaling cascade is the most common tumour-initiating event that occurs in epithelial stem cells and results in the development of sporadic colorectal cancer. Because interference with the gp130/Stat3 signaling cascades limits the expansion of such intestinal (cancer) stem cells, the addiction of colon cancer cells to gp130/Stat3 signaling can be therapeutically exploited in these tumours where targeting of the mutated WNT/beta-catenin signaling cascade is not feasible.

Hck activation

The cellular composition of the tumour microenvironment affects how well a tumour can grow and respond to targeted and immune-modulatory therapy. Although these processes are affected by many different cell types within the tumour stroma, macrophages and other myeloid-derived cells are among the most important players. We have found that the myeloid cell kinase Hck is highly abundant in the tumour microenvironment and aberrant Hck activation suppresses an effective anti-tumour immune response. We are therefore identifying ways by which we can most effectively target Hck to restore and augment anti-tumour immune responses to more effectively kill the cancer cells.