[Truncated abstract] The treatment of childhood acute lymphoblastic leukaemia (ALL) is one of the great success stories of paediatric oncology, transforming a universally fatal disease into one where 75 to 90% of children are now cured. Although in the past survival for children with T-cell ALL (T-ALL) lagged behind that of children with pre-B ALL, the use of contemporary intensified treatment strategies has significantly diminished this difference, with many investigators reporting similar cure rates for both groups of patients. Despite these marked improvements, numerous challenges still face physicians treating children with T-ALL. Firstly, there have been no additional major improvements in outcome over the last decade, despite additional treatment intensification. Secondly, effective regimens remain elusive for treating children with relapsed T-ALL or patients with resistant disease. Finally, there is a need to identify patients currently potentially overtreated and thus unnecessarily subjected to acute and long term toxicities without benefit. A major challenge therefore, is the identification of novel reliable prognostic markers, in order to identify patients at high risk of relapse and conversely those least likely to relapse, to guide therapy appropriately. Children predicted with a high risk of relapse would be candidates for intensification of therapy and/or novel experimental agents. Conversely, patients predicted to be at low risk of relapse could be offered clinical trials using reduced intensity therapy, thereby minimising toxicity. '...' Crucially, the 3-gene predictor was validated in a completely independent cohort of T-ALL patients, also treated on CCG style therapy. Our 3-gene predictor appears to identify a high risk group of patients which require alternative therapeutic strategies in order to attain a cure. This study has also identified a potential novel agent for the treatment of T-ALL, which may be used as an anthracycline potentiator or anthracycline-sparing agent. We hypothesised that genes associated with a relapse signature provide promising targets for novel therapies. We tested the hypothesis that CFLAR, an inhibitor of the extrinsic apoptotic pathway and a member of the 3-gene predictor may be involved in the development of resistance to chemotherapy. To test our hypothesis we used a novel agent, 2-cyano-3, 12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO), previously shown to inhibit CFLAR protein, in two cell lines established in our laboratory from paediatric patients diagnosed with T-ALL. We found that CDDO displayed single agent activity at sub-micromolar concentrations in both cell lines tested. Importantly, minimally lethal doses of CDDO resulted in significant enhancement of doxorubicin mediated cytotoxicity in one of the cell lines assessed. The findings presented as part of this thesis have revealed the value of gene expression analysis of childhood T-ALL for identifying novel prognostic markers. This study has shown that expression profiles may provide better prognostic information than currently available clinical variables. Additionally, genes that constitute a relapse signature may provide rational targets for novel therapies, as demonstrated in this study, which assessed a potential novel agent for the treatment of T-ALL.
| Identifer | oai:union.ndltd.org:ADTP/225934 |
| Date | January 2008 |
| Creators | Gottardo, Nicholas G |
| Publisher | University of Western Australia. School of Paediatrics and Child Health |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Nicholas G. Gottardo, http://www.itpo.uwa.edu.au/UWA-Computer-And-Software-Use-Regulations.html |
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