Blood cancer could be the leading form of cancer deaths by 2035, according to Australia's first strategic action plan.
Acute myeloid leukemia is the deadliest form of blood cancer with a high rate of treatment failure and relapse. Relapsed leukemia has an extremely poor survival of <10%.
Chemotherapy is the first-line treatment for the deadly blood cancer. However, it is not effective against dormant (inactive) malignant stem cells that consequently regenerate a more aggressive leukemia using their unique tumorigenic/stemness characteristics. Ablating leukemia stem cells is critical for successful anticancer therapy.
Over the past 9 years, our lab has generated a body of knowledge in the discovery of therapeutic targets essential for leukemia stem cell characteristics and established evidence of therapeutic efficacy for clinical trials. Most of our research has been published in top scientific journals including Cancer Cell and Blood.
In partnership with industry and close collaboration with clinicians, we are currently converting our research breakthroughs into innovative stem cell-targeted therapies in clinical trials, which will directly benefit patients with the deadly blood cancer.
Acute myeloid leukemia (AML) is a difficult-to-treat blood cancer with a 5-year survival rate of only 27.4% in Australia.
Despite intensive chemotherapy, the majority of patients with AML relapse and ultimately die from their disease.
Clinical evidence has supported the important role of leukemia stem cells in the high relapse rate of AML 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 escaping from cell death. Targeted elimination of leukemia stem cells is now believed to be essential for AML patients to achieve a complete remission.
Our studies have identified key self-renewal pathways (Science 2010; Blood 2014; Leukemia 2016, 2019; Cancer Cell 2020) 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 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 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 at exploring epigenetic mechanisms that govern malignant stem cell function and at discovering 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.
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/signaling 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.
Techniques: 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 (ChIP-seq), flow cytometry, patient-derived xenograft mouse models, in vivo preclinical drug testing, stem cell technologies etc.
Significance: 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, tumor resistance to chemotherapy, and ultimate relapse.