Cancer and Stem Cell Laboratory

The main focus for the Cancer and Stem Cell Laboratory team is to investigate how healthy stem cells are converted into cancer stem cells and to develop effective new therapies that specifically destroy cancer stem cells. These cells, which are often resistant to chemotherapy, are now believed to be the engine driving the growth of cancer and the root cause of therapy resistance and disease relapse.

Stem cells are special cells that are not only capable of giving rise to different types of cells, but can copy themselves indefinitely in a process known as self-renewal. If stem cells become cancerous, they can multiply out of control and cause a tumour. Cancer stem cells have their own protective mechanisms that make them resistant to anti-cancer drugs. After chemotherapy, if even one cancer stem cell is still alive, it can regenerate the entire tumour using its unique self-renewal capacity and the disease can come back. The newly emerged tumour after relapse is often more aggressive and more resistant to chemotherapy. Ablation of cancer stem cells is now considered a promising approach to improve cancer survival and may even lead to a cure.

Over the past nine years, our team has generated a body of knowledge in the discovery of therapeutic targets crucial for leukemia stem cells. We have also established evidence of therapeutic efficacy for clinical trials in relapsed acute myeloid leukemia - a deadly blood cancer with a patient survival rate of less than 10 per cent. Most of our research has been published in top scientific journals including Cancer Cell, Blood and Leukemia. In partnership with industry and in 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.

Focused research areas:

Leukemia stem cell biology
Targeted therapy, including immunotherapy and CAR-T cell therapy
Preclinical drug testing
Functional genomics and epigenetics
Signaling pathways
Cancer metabolism
Cellular barcoding
Single-cell multiomics and CUT and Tag

Current funding sources:

National Health and Medical Research Council
Cancer Australia
Leukaemia Foundation
Cancer Council
Tour de Cure
Industry

Lead

Associate Professor Jenny Wang

Head, Cancer and Stem Cell Laboratory
School of Medical Sciences
Kolling Institute

Jenny is an internationally recognised expert in cancer and stem cell research. She undertook postdoctoral research in leukemia stem cell biology at Harvard Medical School. After publishing her first-author paper in Science and co-author paper in Nature, she returned to Sydney in 2011 and established her own independent stem cell group in 2013. Her research was the first to link Wnt/β-catenin pathway to leukemia stem cells. Her research group expanded this breakthrough finding to link G protein-coupled receptors to β-catenin activation. The seminal discoveries are particularly important because G protein-coupled receptors are targets for 50 per cent of marketed drugs in non-cancer disease but their role in cancer remains unexplored. Her research provides evidence-based repurposing of non-cancer GPCR drugs for cancer therapy. In collaboration with OncoMed Pharmaceuticals USA, her research group has recently demonstrated therapeutic efficacy of GPCR-associated drug in relapsed acute myeloid leukemia, resulting in current translation of the innovative stem cell-targeted therapy into clinical trials to directly benefit patients with deadly blood cancer.

Over the past nine years, Jenny has secured more than $6 million in competitive research funding as a principal investigator, including three NHMRC project grants, along with grants from the ARC, the Cancer Institute, Cancer Australia, Leukaemia Foundation, Cancer Council, Tour de Cure and the Anthony Rothe Memorial Trust. Most of her grant-supported research has been published in the top scientific journals including Cancer Cell. (2nd of 207 in Cancer Research).

Jenny has been frequently invited as a keynote speaker at international conferences and as a reviewer or editor for reputable journals. She has served as a lead scientific advisor on the international clinical advisory board and served on a number of grant review panels, such as NHMRC Ideas, Medical Research Future Fund Stem Cell Therapies Mission and the Victorian Cancer Agency for Early/Mid-Career Fellowship. She has supervised a number of PhD and Honours students who have published in high-impact papers, presented at national and international conferences and received many awards.

In the next five years, a main focus of her research group is to translate the program discoveries into clinical trials for patients with deadly blood cancer, with the ultimate goal of replacing ineffective chemotherapy with effective stem cell-targeted therapies.

People

Dr Nunki Hassan

Postdoctoral Research Associate

Xiangtoa Wei - PhD Student

Kaitlyn Trajcevski - Research Assistant

Ali Zare - PhD Student

Claudia Widjaja - Research Assistant

Gazi Fairooz - Research Project Student

Yang (Henry) Lin - PhD Student

Imogen Cratchley - Honours Student

Likun He - PhD Student

Network

International industry partnership

American Society of Hematology

KCA Education and Training Committee

Projects

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.

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, flow cytometry, patient-derived xenograft mouse models, in vivo preclinical drug testing, and stem cell technologies.

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, tumour resistance to chemotherapy and ultimate relapse.

Publications

https://www.researchgate.net/profile/Jenny-Wang-59/research