We are a group of cancer researchers who are trained in cell biology, immunology, developmental biology and molecular oncology. Our team has made major contributions to the discoveries that defects in cell death can cause cancer, autoimmune disease and impair the response of malignant cells to diverse anti-cancer agents.
Our current work aims to reach a detailed understanding of the molecular control of programmed cell death and tumour suppression more generally. We exploit this knowledge to develop novel treatments for cancer and autoimmune diseases.
The vision of our team is to generate the knowledge that will underpin the development of improved therapies for cancer patients.
Our early work together with other groups at WEHI showed that defects in apoptotic cell death can cause cancer or autoimmune disease and render malignant cells resistant to diverse anti-cancer agents.
Our discovery of the BH3-only proteins and the demonstration that they are critical for the initiation of apoptotic cell death directly underpinned the development of BH3 mimetic drugs, such as Venetoclax which is approved for treatment of chronic lymphocytic leukaemia and acute myelooid leukaemia.
Our group also revealed which cellular responses activated by the tumour suppressor p53, encoded by the most frequently mutated gene in human cancer, are critical to prevent the development of cancer.
We are using genetic (Crispr/Cas9 and shRNA library) screens to identify critical regulators of cell death signalling and tumour suppression by p53. The functions of ‘hits’ from these screens will be identified by generating in vivo laboratory models that lack or over-express these proteins.
We expand substantial effort on clinical translation of our discoveries by collaborating with chemists and structural biologists at the institute, and leading biotech/pharma companies from overseas. Most notably this has assisted in development of inhibitors of pro-survival BCL-2 family members (so-called BH3 mimetics) for cancer therapy.
Undertaken in close collaboration with the Gemma Kelly and Marco Herold labs.
In collaboration with the Kelly and Herold labs we have generated a pair of complementary gene-targeted mice in which we can change cells from a wt p53 into a mutant p53 state and then (strain 1) back into wt p53 or (strain 2) into a p53 deficient state. The analysis of these mice combined with models of lymphoma, lung cancer or pancreatic cancer will inform on how to best develop novel therapeutics to treat cancers driven by mutations in p53 (~50% of human cancers).
Team members: Zilu Wang, Elizabeth Lieschke, Annabella Thomas, Lois Kerswell, Shuai Huang; in close collaboration with the labs of Gemma Kelly, Kate Sutherland and Tracy Putoczki
MCL-1 is a well-known anti-apoptotic member of the BCL-2 protein family. It is an attractive therapeutic target for many cancers because genetic removal or drug-mediated inhibition of MCL-1can kill a broad range of malignant cells. We have generated so-called anti-apoptotic BCL-2 family member gene-swap mice to examine which of the two functions of MCL-1 – inhibiting apoptosis or maximising mittochondrial ATP production, is needed for animal development and adult tissue function. The finding from these studies are critical for the clinical development of MCL-1 inhibitors for cancer therapy.
Team members: Kerstin Brinkmann, Annli Tee, Leonie Gibson; in collaboration with the Gemma Kelly and Marco Herold labs
Our laboratory previously identified factors that are critical for the sustained survival and expansion of different types of cancer cells.
Collaborations with major pharmaceutical companies facilitated the development of so-called ‘BH3-mimetic’ drugs that inhibit these pro-survival factors, called BCL-2, MCL-1 and BCL-XL. We showed that these BH3 mimetic drugs can efficiently kill a broad range of cancer cells. We have found that in tissue culture ‘BH3-mimetic drugs’ can kill human brain cancer cells much more potently than the currently used chemotherapeutics.
With the support of the Cure Brain Cancer Foundation, we have established new models of brain cancer to test and evaluate the potential of BH3-mimetic drugs for the treatment of patients with brain cancer. We are now undertaking pre-clinical studies to test whether these drugs are effective ‘in vivo’. If these studies prove successful, we will engage clinical collaborators to proceed with clinical trials.
Team members: Diane Moujalled, Eiman Saleh
All students and postdocs in my group have clearly demarcated projects. This helps maximise the areas of research that we can tackle. When work within an area needs to be accelerated, help is provided by other members from the lab, particularly research assistants.
We collaborate closely with the Kelly, Sutherland and Putoczki laboratories as well as with many other laboratories within WEHI and many laboratories elsewhere in Australia and overseas.
Many past members of our group are now directors of medical research institutes in Australia (such as Marco Herold, Chief Executive Officer, Oliver Newton John Cancer Research Institute, Melbourne; Marc Pellegrini, Executive Director, Centenary Institute, Sydney), department heads or laboratory heads at WEHI or leading research organisations in Europe or the US.