Novel therapeutic approaches to paediatric cancer
AuthorWood, Paul James
Document TypePhD thesis
Access StatusOpen Access
© 2019 Paul James Wood
The overall cure rates for paediatric cancer have improved dramatically over the last 60 years. There is, however, a subset of paediatric embryonal tumours that carry a poor prognosis. In particular, metastatic neuroblastoma, in association with MYCN amplification, remains difficult to cure. The phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR) cell signalling pathway, as well as epigenetic factors, play a key role in numerous cellular functions including cell growth, survival and angiogenesis. Activation of the PI3K/AKT/mTOR pathway is common in a variety of tumours including those associated with the MYC family of proto-oncogenes. As a result of its multiple cellular functions it is not surprising that deregulation of this pathway is frequently observed in cancer. The importance of MYCN as a therapeutic target, and the impact of PI3K inhibitors in MYCN amplified neuroblastoma has been well documented. Rapamycin and its analogues everolimus (RAD001) and temsirolimus (CCI-779) exert selective cytostatic/cytotoxic effects on by targeting mTORC1. PF-502 is a combined PI3K/mTOR inhibitor that serially inhibits multiple targets within this pathway. Accordingly, interest in both mTOR inhibitors and combined PI3K/mTOR inhibitors as anticancer drugs, with particular applications to neuroblastoma, has recently surged. When used in the aggressive TH-MYCN murine model of neuroblastoma, PF-502 produced a significant survival benefit by both apoptotic and anti-angiogenesis effects whereas temsirolimus worked primarily by an anti-angiogenic effect. Epigenetic modulation of tumours has recently received increasing attention recently. Histone deacetylase inhibitors have shown pre-clinical promise in a variety of paediatric tumours. Specifically, they have been shown to promote both tumour apoptosis and terminal differentiation in other paediatric embryonal tumour pre-clinical models. Accordingly, the role of agents targeting these pathways was studied in the aggressive TH-MYCN mouse model of neuroblastoma. Panobinostat, when given as a continuous, low dose, resulted in a significant survival benefit as a result of both apoptosis and differentiation, with terminal differentiation achieved by prolonged exposure to the drug. Following on from these pre-clinical studies, an open label, Phase I (3+3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumours, including neuroblastoma, was conducted. Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterise its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells (PBMNC). Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples. A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15mg/m2 and was well tolerated. PK data and drug tolerability at 15mg/m2 was similar to that previously published. In summary, pre-clinical experiments support serial inhibition of the PI3K/AKT/mTOR pathway and the use of histone deacetylase inhibitors as treatment approaches in neuroblastoma.
KeywordsNeuroblastoma; Paediatric cancer; PI3K/AKT/mTOR; Histone deacetylase; Targeted therapies; Clinical trial; Translational
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