Team Leader
What we do
Our group aims to understand the molecular mechanisms that cancer cells hijack to become malignant. One such mechanism is epigenetics. Epigenetics encompasses all the molecular changes that occur at the DNA level of a cell that do not actually affect the DNA sequence but do have a direct impact on gene expression to specify that cell’s fate.
Epigenetic mutations and epigenetic therapies
Cancer cells show aberrations in their epigenome and in proteins that affect the epigenome. This results in the inappropriate overexpression of oncogenes and the silencing of tumour suppressor genes. We are investigating the precise mechanisms underlying the development of epigenetic-driven childhood cancers, with the aim of designing novel epigenetic-based therapies based on the specific epigenetic profile of each child with cancer.
Diffuse midline glioma is an epigenetically driven cancer
Diffuse intrinsic midline glioma (DMG/DIPG) is the most common and aggressive brainstem tumour in children, with virtually zero survival and with no effective treatment. From the molecular point of view, DIPG is an epigenetically driven cancer. More than 80% of cases are characterised by global epigenomic alterations caused by a single somatic mutation in the histone H3, called H3K27M, or by the overexpression of the developmental gene EZHIP, a natural mimic of H3K27M. Despite this, existing epigenetic therapy has failed to improve the outcomes of these children, mainly due to a lack of specificity towards the driving epigenomic aberrations that lead to high toxicity and ineffective cure. Our group is investigating the best epigenetic therapeutic strategy that can overcome the past roadblocks of this therapy in DMG/DIPG.
Epigenetics of the Tumour Microenvironment
Tumours are not only made up of cancerous cells, but also contain normal cells of different origins. These form what is known as the tumour microenvironment (TME) and mainly consists of immune cells, fibroblasts and endothelial cells. The interaction between the TME and cancer cells is critical in tumour progression and metastasis, thus targeting these cells is a very compelling therapeutic approach.
Our group is investigating how the epigenome of the cells that make up the TME is re-shaped to promote the metastatic capabilities of cancer cells. Our overarching aim is to use epigenetic-based drugs to specifically target malignant pathways that are activated in the cells from the TME. For example, one of our major interests is to use epigenetic drugs as a new immune therapeutic approach, or in combination with existing checkpoint inhibitors.
Our aims
The overall aims of our team are to:
- define actionable epigenetic targets in DMG/DIPG
- develop new tools for targeted-epigenetic therapy in DMG/DIPG
- characterise the tumour microenvironment in DMG to develop epi-immunotherapy
- define biomarkers for therapy response in diffuse midline glioma.
Research projects
Epigenetic therapy focussed on DMG causes
Contact: Fa Valdes Mora, FValdesMora@ccia.org.au
Our team aims to investigate how H3K27M mutation and the expression of EZHIP affects the epigenome and how it interacts with other epigenetic factors, with the aim of using epigenetic drugs to therapeutically target the downstream epigenetic consequences of H3K27M or EZHIP presence.
Epi Immuno-therapy in Diffuse Midline Glioma
Contact: Fa Valdes Mora, FValdesMora@ccia.org.au
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of tumour-infiltrating immune myeloid progenitors that promote cancer progression and metastasis in many cancer types. Using a preclinical mouse model, we have discovered a transcriptional program that results in malignant recruitment and activation of MDSCs leading to metastasis. It has also been shown that abatement of MDSCs dramatically reduces metastasis. However, due to the high heterogeneity of MDSCs, the phenotype of the pro-metastatic/malignant MDSCs and the underlying mechanisms of their recruitment, expansion and differentiation are still unknown, making MDSC-targeted strategies elusive.
Epigenetic therapy is able to up-regulate immune signalling pathways in epithelial cancer cells, and epigenetic drugs have been found capable of priming and sensitising the host immune response to subsequent immunotherapy. Thus combined epigenetic and immunotherapy holds significant promise for improving patient outcomes. Our team aims to identify the epigenetic characteristics of malignant MDSCs in cancer, to enable the design of epigenetic drugs that can modify MDSCs towards differentiated phenotypes and thus disable their immune suppressive capacity. A combinatorial treatment strategy with epigenetic drugs could sensitize cancers to current immunotherapy.
Team
Team Leader
Research Officers
Yolanda Colino Sanguino
Laura Rodriguez de la Fuente
Research Assistant
Sarah Fox
PhD Student
Afraah Cassim
Honours Student
Emily Dowling
News & blogs
Understanding how brain cancer develops in children holds ke...
International study sheds new light on deadly childhood brai...
Professor David Ziegler awarded prestigious scientific award
Brain cancer in focus: An introduction
Get in touch
Do you have a question about our work? For any enquiries please don’t hesitate to contact us.
