Very little is known about the factors that lead to the development of cancer in children. The overall strategy of the Molecular Carcinogenesis Program is to dissect the mechanisms of cancer initiation and progression and to use this information to develop more effective treatments and prevention strategies for childhood cancer.
Our objectives are to:
• better understand the molecular basis of embryonal cancer initiation
• identify and target the novel oncofactors of MYCN oncogene for neuroblastoma treatment
• develop and characterise the novel small molecule compounds that overcome MYCN-initiated cell-death resistance
• decipher mechanisms of neuroblastoma tumourigenesis using single cell profiling
• develop targeted combination chromatin-modifier therapies for neuroblastoma treatment
Our funding sources include the National Health and Medical Research Council (NHMRC), Cancer Institute NSW and Cancer Council NSW.
Head of Program
HEAD OF TRANSLATIONAL RESEARCH
Dr Daniel Carter
As with most childhood cancers, neuroblastoma, a peripheral nervous system cancer, arises in embryonal cells. In the womb, the development of normal organs requires rapid growth of cells making up the nerves, brain and blood cells. However, this rapid growth must stop once mature nerves or blood cells have formed in their correct place in the foetal body. The embryonal cells, which come together to form the normal organs, are produced in excess of what is required. Embryonal cells not eradicated at this time persist and, in some instances, can later cause childhood cancer.
Very little is known about the mechanisms that cause embryonal cells to persist, or how they undergo further changes that lead to cancer in some children. Using a transgenic experimental model that develops neuroblastoma in a very similar manner to the human disease, we have shown that the expression of a cancer-promoting oncoprotein, MYCN, begins the process of neuroblastoma tumour initiation. We found MYCN expression occurs in specialised nerve cells near the spine in a short time-window soon after birth. These cells would normally undergo cell death very soon after birth.
We have dissected the pathway by which MYCN blocks the normal process of nerve cell death and identified individual components of the death-signal that are altered by MYCN. Our work has pinpointed the exact part of the MYCN protein that is required to cause this effect.
Our research is at a very exciting stage. We have identified a crucial protein mediator of the MYCN signal and a therapeutic target in the disease called ‘FAcilitates Chromatin Transcription’ (FACT). FACT and MYCN expression create a forward feedback loop in neuroblastoma cells essential for maintaining mutual high expression. FACT inhibition by the small molecule Curaxin compound, CBL0137, markedly reduces tumor initiation and progression in vivo. CBL0137 is currently being trialled on adults in Russia and the United States. The next step is to trial it on children here in Australia, which doctors hope to begin in the next 12 months.
Dr Belamy Cheung
For children with high-risk neuroblastoma, the five-year survival rate is 40-50%. Most neuroblastoma patients present with a far advanced disease which doesn’t respond well to conventional chemotherapy, and thus neuroblastoma accounts for 15% of all child cancer deaths. Further, the drugs used to treat children with cancer are older general cancer drugs (used for more than 40 years) which can cause serious acute side-effects on normal growing tissues. The cost of supportive care required to manage the side-effects far exceeds the cost of the chemotherapy. Current drug discovery strategies in the pharmaceutical industry do not focus on child cancer because of its low incidence and because many of the common molecular targets in adult cancers are rare in child cancer. Thus, there is an urgent need for drugs with high specificity for cancer cells but low toxicity for the normal growing tissues of a child. Developing such drugs requires identification and validation of appropriate molecular targets, and the technology and capability to translate that knowledge into new drug discovery.
We have identified a protein called PA2G4 as a novel therapeutic target in these highly malignant tumours. The PA2G4 inhibitor WS6 has shown strong treatment effect in our neuroblastoma mouse models. But despite this remarkable potency, WS6 will likely benefit from combining it with different drugs to minimise toxicity and prevent relapse. Our research will investigate the mechanism by which PA2G4 functions in neuroblastoma and use this to guide development of WS6 combination therapies.
Leukaemia, like neuroblastoma, is an embryonal cancer. It arises in embryonal cells. As a baby develops in the womb, its embryonal cells usually mature to become all the specialised tissues and organs of the body. Under normal circumstances, any embryonal cells left over after formation of these tissues and organs die by a natural pre-programmed process. But sometimes these embryonal cells persist and, in rare cases, go on to become cancerous. What causes a non-cancerous embryonal cell to change into a cancer cell is not well understood.
We have obtained the transgenic mouse model of B-cell lymphoma, a disease closely related to acute lymphoblastic leukaemia of the B-cell lineage. The Eµ-Myc mouse model is based on over-expression of the c-Myc oncogene and mirrors the biology and genetic development of human B-cell malignancies. We aim to investigate the underlying mechanisms that cooperate with c-myc over-expression during the B-cell hyperplasia stage (pre-cancer stage), which contributes to B-cell malignancies and tumourigenesis. The Eμ-myc model is highly relevant for testing in vivo efficacy of compounds identified in laboratory, both in tumour initiation and established tumour treatment.
HEAD OF PROGRAMProfessor Glenn Marshall AM
CLINICAL RESEARCH FELLOW
Dr Toby Trahair
Dr David Restuccia
Dr Hassina Massudi
Dr Zsuzsanna Nagy
Dr Ritu Mittra
Chi Yan Ooi
Dr Marion Mateos