��������Ƶ

I led the team that developed PCR-based technology to detect the presence of residual leukaemia in bone marrow of children after initial treatment for acute lymphoblastic leukaemia (ALL). These studies established my group as one of the leading international teams addressing this issue, showing that molecular detection of minimal residual disease (MRD) in paediatric ALL is a new approach to improving survival. My team was the first to report that relapse in children with ALL involves selection of a pre-existing drug-resistant subclone. This led to the first paediatric clinical trial employing molecular genetic testing to guide treatment in high-risk patients (ANZCHOG Study 8), which enrolled more than 650 children nationally over 10 years and saw the survival rates of children with high-risk ALL increase from 35% to about 70%. This molecular diagnostic testing platform, which my team developed and implemented, is now part of standard of care for children with ALL throughout Australia and now provides residual disease testing on more than 100 Australian children and adolescents annually. Based on the results of this testing, high-risk individuals are now stratified to receive alternate therapies. Research in the past five years by my group has continued to provide insights into relapsed and aggressive ALL, and has further improved detection methodology.

My seminal research on the role of the ABCC1/MRP1 multidrug transporter in neuroblastoma led to the first evidence of the clinical significance of this transporter in any human cancer and subsequently provided the first evidence for the clinical significance of the related transporter, ABCC4 and its ability to confer resistance to irinotecan/CPT-11, a drug now used to treat this disease. This research has led to an important shift in understanding the role of ABC multidrug transporter genes in cancer from one simply associated with drug resistance to one that extends to fundamental roles in tumour biology and maintenance of the inflammatory microenvironment. My team further extended this research on ABC transporter genes to ovarian cancer, leading to insights into the pathogenesis of the disease process and the definition of new clinical approaches.

MYCN amplification is the single most important biologic marker in childhood neuroblastoma. In collaboration with Professor Michelle Haber, my research has highlighted the significance of this oncogene in this disease and provided the first report of MYCN-mediated regulation of ABCC1. Building on this research, we provided the first comprehensive demonstration of a major role for Myc transcription factors in the direct and coordinate regulation (both positive and negative) of a large subset of the ATP binding cassette (ABC) transporter gene family, to which the ABCC genes belong. My team provided strong evidence that ABC transporters play a key role in generating a malignant and drug-resistance phenotype in neuroblastoma, with clinical implications for its treatment. Furthermore, we have also demonstrated that MYCN can contribute to multidrug resistance in cancer through the upregulation of a suite of drug-resistance genes covering a range of chemotherapeutic drugs.

My team also pioneered polyamine inhibition therapy, demonstrating that combining inhibition of polyamine synthesis and transport together with conventional chemotherapy, is highly promising as a therapy for neuroblastoma and potentially other MYC-driven cancers. This has eventuated in one completed international clinical trial in 15 children’s hospitals, one current trial open in 120 hospitals internationally, and two more being planned for neuroblastoma and for brain tumours.