Pre-clinical evaluation of imaging biomarkers of neuroblastoma
Supervisor(s): Drs Louis Chesler and Simon Robinson
Section of Paediatric Oncology and Cancer Research UK Clinical Magnetic Resonance Research Group
Team: Paediatric Drug Development
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Summary
Neuroblastoma is the commonest extra cranial childhood solid tumour and originates in peripheral nerve tissues. It is associated with a poor prognosis in its high-risk form, even when treated with high dose conventional chemotherapeutic agents, making rationally designed, molecularly-targeted compounds essential for improved treatment outcome. MYCN gene amplification occurs in 25% of high-risk neuroblastoma and is associated with an aggressive tumour phenotype, enhanced tumour angiogenesis (formation of a new blood supply) and a poor clinical prognosis. The Mycn oncoprotein is highly expressed in tumour but not in normal tissue, making it an attractive candidate for targeted therapeutics. However, Mycn has been difficult to target directly; hence strategies for attacking its upstream regulatory proteins are being sought. To assess the relevance of MYCN overexpression in neuroblastoma, and to test Mycn-targeted therapeutics, we have constructed a murine transgenic model that faithfully replicates the disease biology of high-risk neuroblastoma by targeting overexpression of MYCN to the neural crest. In this model, tumour origin is spontaneous and occurs in the correct tissue of origin. Furthermore, we have identified several inhibitors of the PI3-kinase pathway that destabilise Mycn protein. The development of targeted inhibitors and relevant pre-clinical cancer models are both major themes of research within the Section of Paediatric Oncology at the ICR.
Many cancers, including neuroblastoma, have derailed activation of PI3-kinase pathway signaling, evidenced by increased phosphorylation of AKT. This is associated with dysregulated tumour growth, enhanced angiogenesis and survival. We have shown that upregulation of PI3-kinase signalling in neuroblastoma stabilises the Mycn oncoprotein through inhibition of n-terminal phosphorylation. Mycn drives proliferation and inhibits differentiation of tumour cells. Our strategy has therefore been to target Mycn with small molecules that inhibit the PI3-kinase pathway. These compounds have shown activity in pre-clinical tumour models of neuroblastoma.
With the development of more targeted cancer therapeutics has come the associated challenge of identifying new non-invasive techniques capable of assessing the tumour phenotype and treatment response. This project is part of ongoing initiatives to identify new candidate drugs for neuroblastoma, which a very strong translational theme and integral links with the early drug development Programme for children and young people at The Royal Marsden NHS Foundation Trust. The project is a prelude to clinical studies in children with neuroblastoma of PI3K pathway inhibitors.
References
- Maris, J.M., et al. (2007) Neuroblastoma.The Lancet Vol 369(9579) p2106-2120
- Weiss W.A. et al. (1997) Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J Vol 16, No 11, p2985-2995
- Guertin, D.A., Sabatini, D.M. (2007) Defining the role of mTOR in Cancer. Cancer Cell Vol 12, No 1, p9-22
- Brindle, K.M., (2008) New approaches for imaging tumour responses to treatment. Nat Rev Cancer Vol 8, No 2, p94-107
- Chesler, L. et al. (2008) Chemotherapy-induced apoptosis in a transgenic model of neuroblastoma proceeds through p53 induction. Neoplasia Vol 10, No 11, p1268-1274
