Targeting leukemia stem cells: the path towards a cure for therapy-resistant cancer
Acute myeloid leukemia is a difficult to treat blood cancer with a 5-year survival rate of only 27 per cent in Australia. Despite intensive chemotherapy, the majority of patients relapse and ultimately die from their disease. Clinical evidence has supported the important role of leukemia stem cells in the high relapse rate of Acute myeloid leukemia patients. Leukemia stem cells reside in a mostly quiescent state and as such they are resistant to chemotherapy. These cells possess several unique features such as self-renewal and the ability to escape cell death. Targeted elimination of leukemia stem cells is now believed to be essential for patients to achieve a complete remission. Our studies have identified key self-renewal pathways for stem cell formation and our exciting new findings of pathway inhibitors provide promising therapeutic opportunities to specifically target leukemia stem cells. This project is designed to understand the mechanisms of action of pathway inhibitors in order to develop effective stem cell-targeted therapies that will benefit patients suffering from treatment resistance and disease relapse.
Epigenetic mechanisms of malignant stem cell regulation
Epigenetic regulation of gene expression plays a crucial role 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 leading to the formation of malignant stem cells and the subsequent development of cancer. Unlike genetic alterations, epigenetic marks can be reversed by treatments with chromatin-modifying drugs, making them suitable targets for epigenetic-based therapies. Our studies have uncovered key epigenetic regulators that contribute to cancer formation and progression. This project aims to explore epigenetic mechanisms that govern malignant stem cell function and discover chromatin-modifying drugs that are capable of reversing cancer-associated epigenetic marks. The outcome of this study will have the potential to develop innovative epigenetic therapies.
RNA-based therapeutics through the control of stem cell fate
The recent discovery of non-coding RNAs (ncRNAs) has dramatically altered our view of gene regulation in cancer. MicroRNAs (miRNAs) are a class of ncRNAs that function to regulate gene expression at the transcriptional and post-transcriptional level, playing a pivotal role in cancer progression and metastasis. Using an integrated miRNA-mRNA expression profiling analysis, we have documented a miRNA regulatory network, whose downregulation is associated with the aggressive phenotype of cancer (Haematologica 2019). This study will investigate how a crosstalk between miRNA regulatory network and epigenetic/signalling pathways determines the fate of stem cells and this will pave the way for developing novel RNA-based therapeutics in effectively destroying malignant stem cells.
Single cell multi-omics technologies (transcriptomics, proteomics and epigenomics), cell-based assays, drug response assays, molecular and cell biology, gene and protein expression, immunofluorescence, gene editing, chromatin immunoprecipitation sequencing, flow cytometry, patient-derived xenograft mouse models, in vivo preclinical drug testing, and stem cell technologies.
Successful completion of these projects will generate new insights into cancer and stem cell biology, identify novel therapeutic targets, and provide preclinical validation of therapeutic potential. These studies therefore have the potential to lead to the development of novel therapies that directly and selectively kill cancer stem cells, which are now considered to be the root cause of disease progression, tumour resistance to chemotherapy and ultimate relapse.