Professor Michelle Haber

The central focus of my research is on transforming child cancer treatment. My team is currently working on the development of new combination therapies, new methods to accurately monitor tumour progression/ evolution, and to further our understanding on the aetiology of child cancer, with potential for offering the first preventative drugs. Our aim is to enable a new era of precision medicine to significantly improve patient outcomes. Described below are some of the major projects we are currently working on:

There is a critical need for more effective and less toxic therapies for children with high-risk solid paediatric cancers such as neuroblastoma, the commonest tumour of young children. My team seek to both understand the biology of neuroblastoma and also to improve patient survival rates through (1) identifying molecular mechanism underlying drug resistance, (2) developing improved pre-clinical testing models for high-risk neuroblastoma (including patient derived xenograft (PDX) models and models of metastatic disease, and (3) modelling personalised medicine strategies including molecular profiling and ex vivo drug sensitivity screening.

Despite intensive treatment, > 50% of children with high-risk neuroblastoma still die from their disease. While anti-GD2 monoclonal antibody immunotherapy has positively impacted survival rates of patients, highlighting the potential for immunotherapeutic approaches to improve outcomes for this disease, too many high-risk patients are still dying, and hence, there is an urgent need to develop new approaches that can harness the full potential for immunotherapies in neuroblastoma treatment. The tumour microenvironment (TME) of solid paediatric cancers is often modified by the cancer cells to be immunosuppressive, allowing cancer cells to escape not only  the patient’s immune system, but also potential immunotherapies. We are interested in combining immunotherapies with novel targeted agents that can reprogram the TME to be less immunosuppressive, potentially changing the treatment paradigm of neuroblastoma away from multimodal treatment protocols heavily based on cytotoxic drugs, in favour of more effective and less toxic immunotherapeutic approaches.

We have identified RUNX1T1, a transcriptional co-repressor, as a driver of childhood neuroblastoma and potentially of other high-risk child cancer. Our data strongly support the development of first-in-class RUNX1T1 inhibitors, and we are currently working on (1) identifying the key proteins that interact with RUNX1t1 that are critical for neuroblastoma formation and progression, (2) determining the role of RUNX1t1 in the progression of other high-risk childhood cancers, and (3) developing RUNX1t1 inhibitors for progression into clinical trial.

My team and I have pioneered four novel therapeutic approaches with significant clinical potential for treating the worst child cancers with particularly poor outcomes, namely, high-risk neuroblastoma; high-grade brain tumours (e.g., Diffuse Intrinsic Pontine Glioma (DIPG)); high-risk/relapsed Acute Lymphoblastic and Myeloblastic Leukaemia; and aggressive sarcomas. These approaches include (1) polyamine inhibition with DFMO/AMXT-1501, (2) targeting the epigenome with CBL0137, (3) inhibiting arginine metabolism with BCT-100, and (4) NAMPT inhibition with OT-82. While each of these therapies have progressed to clinical trial, we are currently working on increasing their clinical potential by incorporating them into optimal combinations for each tumour type which will then be incorporated into our ZERO Childhood Cancer basket trial program and other international trials. We are also working on defining biomarkers to identify the patients most likely to respond, informing eligibility criteria for clinical trials and treatment choices for personalised medicine studies.

I have successfully led the development and roll-out of  ZERO to every Australian paediatric oncology facility, and this program, which is currently available only to children with the most aggressive malignancies, will be made available to every child and young adult with cancer in Australia, by end of 2023. ZERO has improved outcomes for children with high-risk cancers and has transformed the approach of managing high-risk childhood cancers nationally. Currently, treatment recommendations for children enrolled on ZERO are based primarily on comprehensive whole genome sequence analysis of a single surgical biopsy of each child’s cancer. However, we know that tumours can evolve to become resistant to targeted treatments, hence requiring novel approaches to non-invasively monitor tumour mutation and progression in real time, so that we can identify developing drug resistance and change treatment in order to avoid relapse and likely death. I have pioneered a Liquid Biopsy program, involving analysis of circulating tumour DNA (ctDNA) and circulating tumour cells (CTC) in blood and other body fluids, which can harness the whole genome sequencing data from children enrolled on ZERO in order to design highly sensitive patient-specific markers which can be used to detect emergence of treatment-resistant subclones, to monitor cancer burden and the evolving mutational landscape during treatment, and hence guide personalised treatment recommendations throughout the child’s cancer journey.