A pre-clinical approach to the development of targeted therapeutics for paediatric cancers


Session type:

Louis Chesler1
1The Institute of Cancer Research, London, UK


Four common paediatric solid tumours (neuroblastoma, medulloblastoma, rhabdomyosarcoma and glioblastoma) account for the majority of deaths from relapsed, therapy refractory cancer in children. Cure rates have not increased in the last decade, despite the escalation of high-dose conventional chemotherapy and a corresponding increase in long-term toxicity. More effective and non-toxic therapeutics are urgently needed. One barrier delaying the development of novel oncogene-targeted therapeutics for children's solid tumours is a lack of pre-clinical tumour models that fully recapitulate the clinical behaviour of these conditions.

Recent advances in systematic sequencing and profiling of paediatric tumour biopsies has identified disease-associated oncogenes and genomic alterations, which describe a proportion of poor-outcome tumours and can be modelled using genetically-engineered murine (GEM) systems. This presentation will address some of the major developments in GEM modelling for children's solid tumours, such as the identification and tissue-specific overexpression of anaplastic lymphoma kinase (ALK) mutations, which account for a proportion of hereditary and acquired neuroblastomas, tissue-specific overexpression of MYCN, which provides models for high-risk neuroblastoma and medulloblastoma, and new opportunities for modelling of additional targets in other solid tumours.

Another significant roadblock to development of novel therapeutics is the inefficiency of GEM systems for this purpose, and the failure of additional pre-clinical systems such as subcutaneously implanted tumour xenografts to adequately predict clinical efficacy. The application of quantitative pre-clinical imaging technologies, such as ultrasound, magnetic resonance (MRI), computed tomography (CT) and other methodologies has helped to circumvent this issue, when such techniques are applied to pre-clinical trials in a formalised setting. Specific examples of imaging-driven pre-clinical trials will be discussed, both for the development of targeted oncotherapeutics and for assessment of therapeutic resistance to primary chemotherapies.