Radiotherapy is a type of cancer treatment where high-energy radiation, such as x-rays, is directed towards parts of the body to kill cancer cells. Professor Anthony Chalmers and his team hope to increase the effectiveness of radiotherapy in two ways. Firstly, by increasing the ability of radiotherapy to kill neuroblastoma tumours by combining it with drugs which target tumour vulnerabilities. Secondly, by examining the interactions between cells, radiation and drugs the team will uncover new potential targets for therapy
Increasing the susceptibility of neuroblastoma cells to radiotherapy by targeting glycolysis and lipogenesis
Professor Anthony Chalmers
Wolfson Wohl Cancer Research Centre, University of Glasgow
Glasgow, G61 1QH
13 September 2021
Neuroblastoma is a childhood cancer of specialised nerve cells, called neural crest cells. These cells are involved in the development of the nervous system and other tissues. Neuroblastoma is predominantly diagnosed in infancy and affects around 100 children per year in the UK. Half of neuroblastomas are highly aggressive and spread throughout the body at the time of diagnosis. It is characterised either by unresponsiveness to therapy or by early relapse if remission is achieved. High-risk disease, which has an overall survival rate of less than 40%, is responsible for 12% of paediatric cancer fatalities and new treatments are urgently needed.
Neuroblastoma cells express receptors on their surface which allow them to selectively accumulate radiation administered in the form of targeted radiotherapy. Although these radioactive drugs have achieved some success as single agent treatments, the associated bone marrow and kidney toxicities limit the doses that can be delivered. Therefore, it is likely that the most effective way to use these therapies will be in combination with other treatments. The research team have previously demonstrated that targeting characteristics of cancer cells can increase the response to radiotherapy. One such characteristic is abnormal metabolism, particularly the way in which fats and sugars are built up or broken down. These processes provide the energy required for rapid growth of neuroblastoma cells and allow them to evade death after treatment with radiation or drugs. Professor Chalmers’ team believe that the clinical benefit of neuroblastoma-seeking radioactive drugs may be maximised by combination with drugs which target cancer cell metabolism.
Research by the team has previously shown that drugs which interfere with fat and sugar digestion increase the anti-cancer effects of radiation. However, both these drugs and radiation treatment may be hazardous to normal healthy organs. In order to reduce side-effects this project aims to use radioactive drugs which bind only to neuroblastoma tumours (targeted radiotherapy) and use drugs which target the characteristics of cancer cells but not normal cells.
The combination of these two procedures will more effectively kill neuroblastoma and provide insight into increasing the effectiveness of radiotherapy for children. Research using laboratory models to assess drugs which target the abnormal metabolism of neuroblastoma cells to sensitise these cells to radiotherapy, will also be undertaken in this project. The team will determine the combinations of drugs which enable the death, by radiation treatment, of cells grown from neuroblastoma tumours.
The anticipated outcome of this project will be demonstration of the feasibility of increasing the effectiveness of radiotherapy of neuroblastoma by targeting the metabolic characteristics of these tumours. Although targeted radiotherapy of neuroblastoma has produced encouraging results, increasing the dose of radiation given to the patient is not possible because of side-effects. Therefore, it is likely that the administration of radiotherapy will benefit from combination with drugs which enhance the sensitivity of cancer cells to radiotherapy but are not associated with effects on the bone marrow and kidney.
Through long-standing collaboration with paediatric oncologists engaged in the care of patients with neuroblastoma, the team hope to progress positive laboratory findings to the clinic in order to improve the therapy of high-risk neuroblastoma patients. Children with medulloblastoma will benefit from enhanced tumour-killing effectiveness of radiotherapy, without increasing the unwanted side-effects associated with this therapy. Furthermore, this research aims to uncover potential targets which will be the subject of future investigations
The project will be directed by Professor Anthony Chalmers, who has extensive experience in the field of radiation treatment and enhancing the response of tumours to radiotherapy. As a clinician-scientist at the University of Glasgow’s Wolfson Wohl Cancer Research Centre, Professor Chalmers is involved in the translation of laboratory findings into treatments for cancer patients and is currently developing clinical trials evaluating the safe and effective combination of radiotherapy and chemotherapy.
Professor Chalmers’ team includes Dr Oliver Maddocks at the University of Glasgow, whose expertise will allow the use of the most cutting-edge techniques.
Dr Mark Gaze, consultant clinical oncologist at University College London Hospital and Great Ormond Hospital for Children NHS Foundation Trust has expertise in radiotherapy of paediatric tumours and is ideally placed to advise laboratory studies and promote the development of clinical trials in children with neuroblastoma.