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UCL Great Ormond Street Institute of Child Health

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Kathy Pritchard-Jones' Research Group

KPJ lab group3

Introduction

The aim of our research group is to study the molecular biology, pathology and clinical features of paediatric kidney cancers. We are focused on the discovery and validation of both current and new biomarkers; investigating their potential for improving risk stratification for the most and treatment that will allow the development and implementation of novel targeted therapies. Our projects involve collaboration between paediatric clinicians and pathologists, molecular biologists, cell biologists and bioinformaticians.

Background

Up to 90% of paediatric kidney cancers are Wilms tumours (WT) with a prevalence of one in 10,000 children under 15 years. Although several WT-associated genes have been described, most tumours do not harbour mutations in any of these known genes. WT is frequently associated with nephrogenic rests (NRs), presumed precursor lesions representing aberrantly persistent stages of embryonic kidney development. The steps involved in NR retention and their transformation to WT are unknown.

In Europe, WTs are treated with a course of pre-operative chemotherapy prior to surgery (Pritchard-Jones et al. 2012). The surgical specimens are then assessed by histology and clinical staging in order to categorise risk groups (low, intermediate and high) and specify following treatment. Currently, no molecular features aid risk stratification. Whilst the majority of patients survive, 25% require radiotherapy that has an adverse impact on growth and second tumour risk. From these, 50% require the potentially cardiotoxic chemotherapy drug, doxorubicin (Pritchard-Jones et al. 2012). SIOP-RTSG recently completed a 10 year randomized trial concluding that within predefined efficacy margins, it is acceptable to avoid doxorubicin in ~38% of all children with WT (Segers et al. 2011).

Currently, our main challenge is to improve the success of front line therapy whilst minimizing long term side effects, and to find better treatment strategies for ‘high risk’ histology cases. We are using several approaches and experimental designs to find new biological insights to achieve our goals.