Research

Researchers – Professor Graham Cook and Dr Fiona Errington-Mais

The immune system protects us from infections. It ensures that bugs such as coughs, colds and the flu are normally eliminated without making us seriously ill. It is now known that the immune system can also protect us against cancer. Cells of the immune system patrol our tissues and eliminate “rogue cells” that might lead to cancer. However, cancer cells have their own tricks and adapt themselves to evade immunity. Cancers hide from immune cells, or switch them off and therefore continue to grow. By the time a cancer is detected by a doctor, it has already escaped the attention of the immune system. The goal of our research is to find new ways to switch immune cells on so that are able to – detect and destroy cancer cells.

Viruses are good at switching the immune system on and some viruses can infect and kill cancer cells. Using viruses that don’t cause harm to patients can help to attack the cancer in two ways. First, the virus can kill the cancer cells directly. Secondly, the virus switches on the immune system to attack the cancer cells. We are interested in how these viruses, known as oncolytic (“cancer-bursting”) viruses switch on a type of immune cell in the blood, called a natural killer cell. We have shown in lab studies, and in clinical trials, that the oncolytic viruses switch the killer cells on. We now want to try these viruses to see if they can help to kill Ewing’s sarcoma cancers. We have a number of these viruses that have been made at clinical grade, this means they are manufactured specifically for trying in cancer patients. We will test these viruses in the lab to see if they kill the Ewing’s sarcoma cells directly and if they switch on the killer cells to destroy the cancer. In previous research, we have identified molecules that the Ewing’s sarcoma cells use to switch the killer cells off; there are also therapeutic drugs available that block these molecules. We will investigate whether combinations of viruses, this new drug and killer cells together are an effective route to kill Ewing’s sarcoma.

This is a laboratory-based project. However, the viruses and drugs we will use are in clinical trials for other cancers and are generating promising results. By focusing our attention on these existing agents, we can avoid the long development time from lab to clinic. Our goal is to provide information that will encourage the use of these clinical-grade viruses and drugs in clinical trials in the not so distant future. To help us achieve scientific and, ultimately, clinical progress in this area, we have assembled a team of scientists and clinicians with expertise spanning the laboratory and clinical aspects of the work.

Researcher – Professor Sue Burchill

Unlike many cancers where targeted therapies have led to significant improvement in outcomes for young people, there have been few advances in the treatment for Ewing’s sarcoma in the last three decades. Currently just 1 in 5 young people with the most aggressive form of this cancer survive to 5 years, and late relapse remains a significant concern. This, combined with the fact that patients’ currently face debilitating treatment emphasises the need to accelerate novel treatments into early phase clinical trials.

The shortage of targeted therapeutics being evaluated in Ewing’s sarcoma somewhat reflects the lack of knowledge of what is driving those tumour cells leading to relapse, and the variability in the behaviour of different Ewing’s sarcoma cells (so-called tumour heterogeneity). Even within a single tumour not all Ewing’s sarcoma cells are the same, which explains why relapse can arise following seemingly successful initial treatment and good responses. Improved models that faithfully represent the clinical behaviour and diversity of Ewing’s sarcoma are therefore essential to identify, evaluate and prioritise candidate new treatments.

In recent studies, we have used functional assays to isolate and characterise self-renewing chemotherapy resistant Ewing’s sarcoma cells. Through these studies we have prioritised targets that could lead to the development of more effective treatments to eradicate the most aggressive cells, which we believe are responsible for driving the tumour. The results are very promising and endorse the approach we have taken so far. However, other non-tumour cells within and adjacent to the tumour can alter how the tumour grows and responds to treatment. We aim to develop a multicellular preclinical model combining Ewing’s sarcoma and normal cells from the tumour microenvironment, to evaluate the effect of new candidates for the development of more effective treatment.

This project will generate a unique preclinical tool combining Ewing’s sarcoma and tumour microenvironment cells for testing and prioritising different treatments. In the future we will propose this model as part of an international preclinical analysis pipeline which we hope will lead to much needed harmonization of studies to evaluate potential new treatments. Such a pipeline would enable results from different research groups to be meaningfully compared and accelerate the prioritisation of compounds for early phase clinical trials.

The Children’s Cancer Research Group is looking studying Ewing’s sarcoma cells to try to find out more about the cells and what it is about them that may be responsible for the disease progressing and re-occuring. We call the cells that they are looking into, Ewing’s sarcoma stem-like cells and they are thought to be resistant to current treatment and re-populate the tumour at primary and secondary (metastatic) sites. If we can destroy these stem-like cells we think that it is likely that we can improve outcomes for some people with Ewing’s sarcoma. The director of the Children’s Cancer Research Group is Professor Sue Burchill and you can read her full article below:

“Previously, and with support from BCRT the Children’s Cancer Research Group at the Leeds Institute of Cancer and Pathology had been awarded a research grant to isolate and investigate the characteristics of Ewing’s sarcoma cells that may be responsible for disease progression and relapse.

These so called Ewing’s sarcoma stem-like cells are thought to be resistant to current treatment and re-populate the tumour at primary and secondary (metastatic) sites. The eradication of these cells is therefore anticipated to improve outcomes for some people with Ewing’s sarcoma. Superior outcome is a priority area where ESRT want to see improvements, and so ESRT were pleased to fund this ground-breaking research.

In the first year of the project the group in Leeds have, in specified laboratory culture systems, succeeded in isolating and maintaining Ewing’s sarcoma stem-like cells taken at diagnosis. This success has prompted the research team to apply for further funding and ESRT has been happy to continue to support this research.

This new funding will allow the team to complete the profiling of these cells, and begin to isolate and characterise Ewing’s cells at relapse.

Reliable methods to identify the Ewing’s sarcoma cells that do not respond to current treatment and are responsible for relapse may lead to the development of tests for the early identification of people for who current therapies are failing. In the future this might help to offer more personalised treatment, selecting and adapting therapy depending on the characteristics and response of the patient to improve cure rates and minimise side-effects.

Professor Sue Burchill, director of the Children’s Cancer Research Group, said ‘We are very grateful to ESRT and their supporters for funding this exciting research project. Without their backing the timely continuation of this innovative work would not have been possible.”

ESRT is delighted to be able to continue its funding of this important research being carried out by the Children’s Cancer Research Group in Leeds.

When treatment options in the UK became limited for their daughter, Elin’s parents begun raising money to fund treatment in the United States. The treatments gave Elin and her family options and hope, but sadly the treatments available were not enough to help her. Elin’s parents were determined to use money raised to address the desperately limited treatment options for children and young people in Elin’s position. They wanted to fund a suitable project in memory of their brave young daughter and they found this with the work of Professor Janet Shipley, whose team at the Institute of Cancer Research are focussed on finding more effective and less toxic treatments to offer children and teenagers with rare sarcomas, such as Ewing’s sarcoma. You can read the full article below:

“In the early hours of 22 May 2015 Elin Rose lost her 4 year battle with Ewing’s sarcoma.

When treatment options in the UK became limited Elin’s parents, Sian and Martin, begun raising money to fund Elin’s treatment, which was likely to take her to the United States. Family and friends rallied round and with the support of the Ewing’s Sarcoma Research Trust a significant amount of money was soon raised.

The fundraising gave Elin and her family options, hope and access to treatments that might otherwise not be available. Elin travelled with her family to receive treatment in the United States, but sadly the treatments available were not enough to help her.

Elin’s parents were determined to use money raised to address the fact that treatment options for children and young people in Elin’s position are so desperately limited. They also wanted to fund a suitable project in memory of their brave young daughter

So Sian and Martin have collaborated with Professor Janet Shipley, who is leading a team at the Institute of Cancer Research (ICR). Professor Shipley’s team are determined to find more effective and less toxic treatments to offer children and teenagers with rare sarcomas, such as Ewing’s sarcoma.

Professor Shipley is one of the world’s leading experts on the biology of sarcomas. Her research aims to support the development of new drugs – or identify existing drugs – that will specifically block the effects of gene aberrations that drive specific types of sarcomas and improve outcomes for teenagers with cancer.

Sian and Martin join a number of parent-led charities who have tragically lost their child to sarcoma and who are now supporting research. This research aims are to improve the treatment of patients with sarcoma that have a poor prognosis. New and better treatment strategies using more targeted therapies are required for Ewing’s sarcoma. These will be derived from research into the underlying genetics and molecular biology of childhood cancers, so this is where Professor Shipley is focusing her efforts to improve our understanding of the genetics and molecular biology of particular tumours.”

As part of our support to the important research being carried out by Professor Sue Burchill and her team at the Children’s Cancer Research Group, in 2016 we purchased a ViCELL XR machine. This machine is vital to their research and is helping them understand how Ewing’s sarcoma cells may become resistant to chemotherapy. With it they can screen potential new small molecules targeting the drug resistant cells and prioritise the new molecules for further development towards clinical trials and you can read her full article below:

“ESRT continues to provide financial support for important research being conducted by Professor Sue Burchill and her team at the Children’s Cancer Research Group, Leeds Institute of Cancer and Pathology.

In 2016 the charity purchased a ViCELL XR machine to support this important work and here one of Professor Burchill’s colleagues, Dr. Elizabeth Roundhill, tells us how they use this machine and what it does.

How does the ViCELL XR work?

This is an automated counter of viable cell number; this cell analyser uses the trypan blue exclusion assay to accurately determine cell viability, cell number, and cell size. The XR model has a wide size range (2-70um), allows rapid analysis, works on small samples so reduces running costs compared to other assays and the image capture technology is improved compared to previous models.

Dead cells appear as small blue circles and are non-viable. Dead cells appear blue because they take up a blue dye. The cells that are alive cannot take up the dye and appear colourless.

What do we use the ViCELL XR for?

The machine is important for current and future translational and fundamental biological research. It provides an accurate, objective, automated, quantitative readout of viable cell number, viability and size.

The ViCELL XR has been particularly valuable for studies to understand how Ewing’s sarcoma cells may become resistant to chemotherapy. In particular, it allows researchers to screen potential new small molecules targeting the drug resistant cells, and therefore prioritise the new molecules for further development towards clinical trials.”

The National Ewing’s Multi-Disciplinary Team (‘NEMDT’) exists to improve the treatment of patients with Ewing’s sarcoma. It brings together UK clinicians to discuss the management of patients with Ewing’s sarcoma. It enables a highly effective exchange of good practice and development of consensus in the best treatment of patients with Ewing’s sarcoma. Since its establishment it has discussed over 200 patients. As the NEMDT is not funded, the ESRT has paid for a one-year fellowship to help develop and increase the effectiveness of the NEMDT. Dr Jessica Bate, Consultant in Paediatric Oncology, took up the fellowship and began reviewing the work of the NEMDT, the use of current collated data and analyse these to determine any impact upon survival rates. You can read more below:

“The National Ewing’s Multi-Disciplinary Team (‘NEMDT’) is a unique national forum which exists to improve the treatment of patients with Ewing’s sarcoma.

It was created in 2011 as a result of the publication of the results of a European clinical trial. This trial demonstrated superior survival rates among patients treated in Germany than those treated in the UK. Further analysis suggested that less consistent and differing approaches to treatment of the primary tumour (i.e. surgical removal and/or radiotherapy) led to this discrepancy in survival rates.

The NEMDT brings together clinicians from across the UK and all relevant specialties (including core medical and surgical members) to discuss the management of patients with Ewing’s sarcoma. In doing so, it enables a highly effective exchange of good practice and development of consensus in the best treatment of patients with Ewing’s sarcoma. Since it was established the NEMDT has discussed over 200 patients.

It is suggested that the above model has demonstrated a positive impact and provides a highly valuable collection of clinical data for analysis by clinical experts.

As the NEMDT does not have access to the necessary funding, ESRT has funded a one year fellowship to support the development of, and increase the effectiveness of, the NEMDT by providing the necessary resources to:

1. review its work to date;
2. review the use of collated data; and
3. analyse the available data to determine any impact upon survival rates.

The fellowship is expected to have a highly positive impact in developing the NEMDT and consequently improving the management and treatment of patients with Ewing’s sarcoma in the UK.

Dr Jessica Bate, Consultant in Paediatric Oncology, University Hospital Southampton has taken up the fellowship and will:

• design a study to review the experience of the NEMDT and its members to date;
  analyse the available clinical data;
• compare NEMDT database data with the specification for Cancer Outcomes and Services Database;
• establish the ability to download relevant information onto the National Cancer Registration Service for England; and
• produce one or more clinical scientific papers about Ewing’s sarcoma.

At the end of the fellowship we aim to have a better understanding of the effectiveness and functioning of the NEMDT, and clearer ideas about how it should develop.”

ESRT is delighted to be funding this important work to support the NEMDT to improve the outcomes for patients being treated for Ewing’s sarcoma.