Cancer and Stem Cell Biology
Our main research focus is to develop new therapeutic strategies specifically targeting and destroying cancer stem cells. These cells are often resistant to commonly-used cancer therapies such as radiation therapy and chemotherapy. They are now believed to be the engine driving the growth of a tumour and the root cause of treatment resistance and relapse in cancer.
Stem cells are capable of dividing indefinitely to produce copies of themselves (self-renewal) and generate multiple cell types. Genetic and epigenetic abnormalities enable cancer stem cells to hijack normal stem cell self-renewal mechanisms and multiply out of control, causing cancer. Cancer stem cells can evade chemotherapy and re-initiate tumour growth through their self-renewal capacity, leading to relapse. Cure of cancer would require the eradication of cancer stem cells from which the disease originates. Targeted disruption of abnormal stem cell self-renewal represents a new therapeutic strategy that could significantly reduce a tumour's capacity to regenerate after treatment. This is becoming a central focus in new drug development.
Our objectives are to:
• understand the mechanisms by which genetic and epigenetic events are required for transforming normal stem cells into abnormal stem cells
• investigate the interaction between the bone marrow microenvironment and normal/abnormal blood stem cells
• uncover key oncogenic self-renewal genes and pathways as novel therapeutic targets
• identify clinical agents selectively targeting blood cancer (leukaemia) stem cells without harming normal stem cells.
Our funding sources include the National Health and Medical Research Council (NHMRC), Cancer Council NSW and Anthony Rothe Memorial Trust.
Dr Jenny Wang
Acute myeloid leukaemia (AML) is an aggressive blood cancer with a five-year survival rate of only 24%. Despite intensive chemotherapy, most patients with AML relapse and ultimately die from their disease.
Clinical evidence has highlighted the important role of leukaemia stem cells in the high relapse rate of AML patients. Leukaemia stem cells reside in a mostly quiescent (resting) state and, as such, are resistant to commonly used anti-proliferation cytotoxic agents. These cells possess several unique features, including increased self-renewal, blocked differentiation and escaping from cell death. These features are caused by aberrant expression of oncogenic driver genes and can distinguish leukaemia from normal stem cells. Targeted elimination of leukaemia stem cells is now believed to be essential for patients with AML to achieve complete remission.
Our studies have identified key oncogenic self-renewal pathways (eg beta-catenin and GPR84) for AML stem cell formation. Our exciting new findings of pathway inhibitors provide promising therapeutic approaches and opportunities to specifically target leukaemia stem cells. This research is designed to understand the mechanism of action of these inhibitors in order to develop more efficient leukaemia stem cell-targeted therapies. This study will generate new insights into leukaemia stem cell biology and provide pre-clinical validation of therapeutic potential.
Dr Jenny Wang
Epigenetic regulation of gene expression plays crucial roles in stem cell functions. Inappropriate maintenance of epigenetic ‘marks’ that sit on the nuclear DNA of cancer cells and control the activity of genes results in activation of oncogenic self-renewal pathways. This leads to the formation of leukaemia stem cells and subsequent development of leukaemia. Unlike genetic alterations, epigenetic marks can be reversed by treatment with chromatin-modifying drugs, making them suitable targets for epigenetic-based therapy.
Our preliminary studies have identified several new chromatin modifiers that contribute to leukaemia formation and progression. This project aims at exploring epigenetic mechanisms that govern leukaemia stem cell functions and to discover chromatin-modifying drugs that are capable of reversing cancer-associated epigenetic marks. The outcome of this study will identify epigenetic targets crucial for leukaemia stem cell survival with the potential to develop novel epigenetic cancer therapies.
Dr Jenny Wang
The recent discovery of noncoding RNAs has dramatically altered our view of gene regulation in cancer. Noncoding RNAs can serve as regulatory molecules, playing a pivotal role in cancer progression and metastasis. Despite increasing evidence highlighting their importance in cancer, understanding of noncoding RNAs is still very limited.
Our preliminary data have identified new noncoding RNAs and uncovered a complex RNA regulatory network. This study aims to understand the regulatory mechanism of noncoding RNAs in leukaemia stem cell biology. The knowledge gained from this study will provide compelling evidence for developing novel RNA-based therapeutics targeting leukaemia stem cells.
Dr Jenny Wang
The bone marrow niche is a local microenvironment that supports blood-cell formation (haematopoiesis) and allows a stem cell to maintain its ‘stemness’ property. Changes in the haematopoietic microenvironment could cause stem cell dysfunction and as a result, lead to haematopoietic malignancies.
Increasing evidence suggests leukaemia stem cells also require support from the bone marrow niche to maintain their self-renewal capacity. Our previous studies have shown that pre-leukaemia stem cells can home to and engraft the bone marrow niche, suggesting that stem cell – niche interactions are required for leukaemia initiation. The objective of this research is to identify critical events capable of converting a normal stem cell niche into a leukaemia stem cell niche and to investigate genetic and epigenetic regulation of the niche and its associated stem cells. Understanding this oncogenic process would permit development of new therapeutic strategies targeting the leukaemia stem cell microenvironment.
This research will generate new insights into cancer stem cell biology, identify new therapeutic targets, and provide preclinical validation of therapeutic potential. It has potential to lead directly to the development of new therapeutic strategies that directly and selectively kill cancer stem cells, which are now considered to be the root cause of tumour resistance to chemotherapy, relapse and disease progression.
GROUP LEADERDr Jenny Wang
Dr Estrella Gonzales
Dr Patrick Connerty