Professor Louis Chesler, The Institute of Cancer Research
Neuroblastoma has a high-risk form that is essentially incurable. Current treatments are mostly ineffective against this form of the disease, which spreads around the body and becomes treatment resistant. Professor Chesler is exploring the mechanisms underlying disease-spread and treatment-resistance in order to develop more effective treatments.
Amount of grant: £251,989 | Date of award: July 2016
Neuroblastoma is a childhood cancer that originates in developing nerve cells. It is the second most common solid tumour to occur in children, affecting up to 100 children every year in the UK. Most of these children are under the age of five years.
Although most patients with neuroblastoma respond to conventional treatment (chemotherapy, radiotherapy and surgery), around 40 per cent of patients have a high-risk form of the disease that is essentially incurable. Most children with high-risk disease die with widespread (metastatic) and treatment-resistant tumours within three years, even after receiving all presently known treatments including drugs, radiation, surgery and immunotherapy.
If we are to develop more effective drugs, which can overcome metastasis and treatment-resistance, we first need to understand the mechanisms underlying these processes of spread and resistance.
Several attempts to explore metastasis and drug resistance have been carried out on human tumour cells grown in dishes, but it is impossible to develop a proper understanding of these complex problems in this way. In the body, tumour cells grow in a complex, 3D microenvironment that alters how they respond to drugs and limits their spread to other tissues. The team at The Institute of Cancer Research (ICR) have developed the first experimental (animal) system, in which neuroblastomas form naturally, in the identical locations to tumours in children. They have now established that after giving them treatment with chemotherapy, these tumours become drug-resistant and spread to the bones exactly the way they do in children.
This is a very significant discovery for children with neuroblastoma, as it means that we can, for the first time, study how these tumours interact with their microenvironment to grow, become drug-resistant and spread.
Professor Chesler and team will use their new cancer models to compare naturally developing tumours that they have made resistant to chemotherapy, with those that are untreated, or are still sensitive, in order to identify the gene and protein changes that cause conventional drugs to become ineffective. They will then toggle these genes on and off to prove that they cause resistance to develop. Finally, they will use targeted next-generation cancer drugs to reverse the resistance and kill these cells.
They will also study tumour cells that spread to the bone marrow after treatment, to identify the genes and proteins required for these cells to survive. They will switch individual genes on and off to determine whether this kills the cells and will use the extensive range of cancer drugs developed at ICR to target these genes to identify the best drugs that could go forward to clinical use.
Professor Chesler is confident that this innovative work will enable them to identify a new generation of targeted-cancer drugs that effectively target the residual, metastatic and treatment-resistant cells that grow to ultimately kill children with neuroblastoma.
About the research team
The research team and the associate investigators are world-leaders in their respective fields and the Primary Investigator’s research with this animal model is widely known and respected within the neuroblastoma research community. External reviewerThis work is being led by Professor Louis Chesler, Professor of Paediatric Cancer Biology at The Institute of Cancer Research (ICR) and Consultant Paediatric Oncologist at the Royal Marsden Hospital (RMH).
In the last eight years, Professor Chesler’s team at ICR and RMH has developed innovative cancer models and powerful, next-generation, gene-targeted drugs that are effective as pills and are without side effects for children with cancer. Some of these drugs produce longstanding cancer-free intervals or even cures.
The team’s approach, to make cancer models driven by a single gene that promotes early formation of tumours, then unravel how these genes act to drive cancer, and then to use next-generation drugs to target these genes, was highlighted in the BBC programme Panorama “Can you cure my cancer?” The programme featured one of their patients who was effectively cured by this approach. Within five years, they moved from identification of a gene to clinical trials that are truly ground-breaking.
Professor Chesler is part of a team at the ICR and RMH that together have taken 16 new drugs to clinical trial since 2005. Although they are starting to succeed with new drugs that target genes driving cancers like neuroblastoma, they have not yet developed any understanding of how residual cancer cells spread and hide in sites like bone marrow to evade treatment. In this project, they will take the next step to identify and target this problem and, in so doing, hope to succeed with drugs that expand the lifespan of children with neuroblastoma.
What difference will this project make?
The formation of acquired resistance is a major obstacle in the design of more effective anti-neuroblastoma therapies. Hence, the project tackles a very important problem.
External reviewerThe prognosis for children with high-risk neuroblastoma is exceptionally poor; most young patients
die with metastatic and treatment-resistant tumours within three years, despite intensive multi-modality treatment. Those who survive can suffer serious lifelong side-effects from the aggressive treatments used.
Safer, more effective treatments are desperately needed for these young patients.
Professor Chesler anticipates that the work being carried out under this project will provide important insights into the mechanisms underlying chemo-resistant regrowth and spread of neuroblastoma cancer cells and that it will help to identify safe and effective new drugs that selectively target these two mechanisms. He anticipates moving a drug to clinical trial within five years, giving a much-needed new treatment option for children with high-risk neuroblastoma.
Read more: About neuroblastoma | Other neuroblastoma projects