Novel therapeutic approaches to childhood leukaemia and solid tumours
Working collaboratively with his group, Professor Vaskar Saha has been involved in developing a network of over 20 countries under the European framework. This group, called IntReALL, is both running a clinical trial as well as developing novel biological tools directed at employing state of the art technology to understand the basis of therapeutic failure. This includes developing links and collaborations with other networks in biology and physical sciences.
Though treatment for children with acute lymphoblastic leukaemia (ALL) is highly successful in the West, it does not readily translate to countries with fewer resources. Similar to the approach that has been successfully established in Europe, Professor Saha has been involved in developing a network in India called ICICLE (Indian Childhood Collaborative Leukaemia Group). Currently this group is investigating whether cutting edge technology can be applied to deliver cost effective therapy with minimal toxicity to children in India. This effort is a collaboration between The University of Manchester and the Tata Medical Centre in Kolkata, India.
The principle areas of research on solid tumours within this group (led by Dr Guy Makin) are around new drug development, particularly of mechanism based therapeutics. The group has evaluated 6 mechanistically different anti-cancer agents since 2006, and established a pathway for rapid pre-clinical evaluation of potentially interesting new agents. Their work with RH1 provided a template for CRUK Drug Discovery Office to sponsor phase I studies of novel agents in children.
The group has established a robust paediatric cell line panel for evaluation of novel agents, and has also developed a subcutaneous mouse xenograft platform for neuroblastoma and Ewing’s sarcoma, and more recently an orthotopic mouse model of metastatic osteosarcoma.
They are also interested in refining systems for pre-clinical evaluation of novel agents and have a collaboration with Professor Muhammad Zaman in Biomedical Engineering at Boston University to develop a high throughput imaging-based system of monitoring tumour cell response to therapeutics. This will allow evaluation of drug effects on cellular motility and matrix invasiveness as well as on proliferation and cell death. These cellular parameters are becoming more important as we start investigating novel agents, such as the Src kinase inhibitor AZD0530, which do not have anti-proliferative effects.
Further research is taking place in cellular therapy approaches to neuroblastoma with an active collaboration with Dr David Gilham in the Clinical and Experimental Immunotherapy Group to develop novel chimeric antigen receptors (CARs) to allow selective T-cell targeting to neuroblastoma cells. In addition there is an ongoing collaboration with Dr Rob Falconer at the Institute of Cancer Therapeutics at the University of Bradford looking at the potential use of polysialyltransferase inhibitors to prevent metastases in neuroblastoma.
The Centre is also active in clinical trials in solid tumours; through Dr Martin McCabe we have developed and lead the EU funded International Randomised Controlled Trial of Chemotherapy for the Treatment of Recurrent and Primary Refractory Ewing Sarcoma – reeCUR, aiming to recruit 475 patients from almost every European country over a 5 year period.
We are also part of the PEPtalk 2 study of prophylaxis against varicella (collaboration lead by Professor Paul Heath, St George’s, University of London) and the MAGIC study looking at cisplatin-induced nephro-and oto-toxicity (collaboration lead by Professor Barry Pizer, Alder Hey). Finally, Manchester (through the Royal Manchester Children's Hospital) is the lead centre for the paediatric network ECMC, bringing all 9 UK phase I centres together as a single network centre, with Dr Guy Makin as the national lead.