Understanding drug-resistance mechanisms in high-risk neuroblastoma

10 October 2016

Dr Suzanne Turner, University of Cambridge

Resistance to treatment has always been a major barrier to curing cancer. This project focuses on treatment resistance in a particular form of high-risk neuroblastoma and aims to proactively identify effective counter-strategies against resistant tumours with the aim of extending relapse-free survival periods.

Amount of grant: £223,310 | Date of award: July 2016


Neuroblastoma is the second most common solid tumour to occur in children, affecting around 100 children a year in the UK. A cancer of the nerve cells, usually developing in the abdomen, it accounts for more than 10 per cent of deaths from childhood cancer.

Despite improvements in overall survival from neuroblastoma, survival in patients in the high-risk or relapse categories has remained at 40 to 50 per cent since the 1970s.

A sub-set of around 9 per cent of high-risk neuroblastoma patients carry mutations in a gene known as ALK, causing patients to produce a protein only otherwise seen in the developing foetus.

The ALK mutation is also seen in a number of adult cancers including ‘non-small cell lung cancer’ (NSCLC). Therapies designed to target the mutant ALK protein in NSCLC patients have shown excellent results in clinical trials, with the majority of patients responding well. The average progression-free survival (PFS) period, defined as the length of time during which the disease does not worsen, increased from three months with standard chemotherapeutics to 7.7 months with the addition of ALK inhibitors. Whilst the PFS period more than doubled, however, it was still limited to less than eight months due to the emergence of tumour cells that were resistant to the ALK inhibitor drugs.

Neuroblastoma patients whose tumours carry ALK mutations are also now being enrolled onto these trials and, as for the NSCLC patients, resistant-tumours are expected to emerge.

In this project, Dr Turner is aiming to identify neuroblastoma-specific resistance mechanisms to ALK inhibitors in order to inform the development of strategies to overcome resistance.

This will build on previous work by the Turner group, in which they have generated a list of candidate genes that may be involved in resistance to ALK inhibitors. Every candidate on that list will be individually tested to confirm its role in the development of resistance. The team will then work to develop clinically-viable strategies to overcome this resistance.

About the research team

Dr Turner is a very experienced investigator who has worked in the ALK field for a number of years…. There is no doubt that the PI and co-PI will be able to carry out the proposed experiments without difficulty.
External reviewer
Dr Suzanne Turner is a Senior Lecturer in the Department of Pathology at the University of Cambridge. She has over 20 years of research experience and has established herself as an internationally-recognised expert on ALK-related malignancies. She is currently leading an EU-funded initiative, named ALKATRAS, focused on enhancing our understanding of the ALK protein and its related malignancies as well as on developing clinically-viable strategies against ALK-linked tumours. Her expertise and broad network in the field of ALK biology will help ensure the success of this important project.

The co-investigator on the project is Liam Lee, a PhD student in the Department of Pathology. Mr Lee has over 10 years of research experience, primarily in cancer biology with an emphasis on molecular genetic technologies. He has acquired cutting-edge concepts and techniques on genetic manipulations from his previous fellowships at leading US institutions, including MD Anderson Cancer Center and the National Cancer Institute. His expertise in genetics and bioinformatics, the science of analysing complex biological data with computer scripts, has played a central role in the design of this study.

What difference will this project make?

Resistance to treatment has always been a major obstacle to successfully curing cancer. Types of cancer with unfavourable survival rates, including high-risk neuroblastoma, tend to respond initially to intensive treatment regimens but resistant tumours invariably develop, causing the patients to relapse and die.

The conventional approach to investigating resistance to a specific treatment is a ‘wait-and-see’ approach where several rounds of clinical trials would be conducted, and the gene mutations developed during the treatment period would be reported and investigated to identify their potential role in the resistant tumour cells.

This ‘wait-and-see’ approach incurs a considerable delay in the development of strategies to counter the resistant tumours. This usually means that there is no strategy for the management of the first patients who go through the trial and relapse.

By proactively investigating resistance mechanisms while the first clinical trials are simultaneously being conducted in neuroblastoma patients, Dr Turner aims to develop tailored therapeutic strategies against resistant neuroblastoma tumours thereby preventing relapse and significantly extending the survival period of young patients.

Read more: About neuroblastoma | Other neuroblastoma projects


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