Pre-clinical evaluation of novel anti-leukemia therapies
Research type
Research Study
Full title
Pre-clinical evaluation of novel therapies for childhood acute lymphoblastic and acute myeloid leukaemias
IRAS ID
133130
Contact name
Philip Ancliff
Contact email
Sponsor organisation
Great Ormond Street Hospital
Research summary
Summary of Research
This is a laboratory-based study using pseudoanonymised tissue and data from existing studies. All consents will be collected under two existing studies. The project requires ethical review as this is a condition in the consent forms for these studies.
Although around 80% of children who suffer from paediatric leukaemia are now living for more than five years after treatment, it remains one of the biggest killer diseases of children. Research in our laboratory is based upon finding new treatments through understanding paediatric leukaemia at the molecular level. We and others have discovered a number of cellular pathways, such as STAT3 signalling, that are essential for the progression of specific paediatric Acute Lymphoblastic Leukaemia (ALL) and Acute Myeloid Luekaemia (AML) subtypes. We have shown that these pathways can be targeted chemical inhibitors, resulting in death of leukaemia cells.
Further work is required in order to assess efficacy of targeting these pathways in primary leukaemia samples. This study aims to establish which subtypes of paediatric ALL and AML are susceptible to such targeting. In addition, we plan to perform pre-clinical evaluation in order to determine how effective the treatments are at eliminating engrafted primary patient leukaemia samples from transplanted immunodeficient mice. These pre-clinical models represent the only currently available approach to examining susceptibility of human leukaemia cells to therapeutic agents in vivo, prior to clinical trials in patients themselves. They will offer us the possibility of establishing bioavailability and toxicity of the inhibitory reagents, at the same time as determining their effectiveness at leukaemia elimination from tissue sites of leukaemia engraftment, such as bone marrow. This work will provide critical information that is necessary in order to translate our experimental models and inhibitory reagents into therapeutic approaches that can be developed for use in clinical trials and future anti-leukaemia therapies.
Summary of Results
Although around 80% of children who suffer from paediatric leukaemia are now living for more than five years after treatment, it remains one of the biggest killer diseases of children. Research in our laboratory is based upon finding new treatments through understanding paediatric leukaemia at the molecular level. We and others have discovered a number of cellular pathways, such as STAT3 signalling, that are essential for the progression of specific paediatric Acute Lymphoblastic Leukaemia (ALL) and Acute Myeloid Luekaemia (AML) subtypes. We have shown that these pathways can be targeted chemical inhibitors, resulting in death of leukaemia cells. Further work was required in order to assess efficacy of targeting these pathways in primary leukaemia samples.
The present study was a laboratory based study using pseudoanonymised tissue and data from existing studies. This study aimed to establish which subtypes of paediatric ALL and AML are susceptible to such targeting. In addition, we planned to perform preclinical evaluation in order to determine how effective the treatments are at eliminating engrafted primary patient leukaemia samples from transplanted immunodeficient mice. These preclinical models represent the only currently available approach to examining susceptibility of human leukaemia cells to therapeutic agents in vivo, prior to clinical trials in patients themselves.
In this study, we successfully engrafted 57 patient samples - both ALL and AML samples. The samples reflected a good representation of the patient population being treated in GOSH. We have used these leukaemia models to demonstrate the effectiveness of drugs that inhibit STAT3 signalling at killing leukaemia cells. Furthermore, we have shown that this therapy can work even better when combined with another drug that is currently in clinical trials for various types of cancer. The leukaemia models we have generated are extremely susceptible to this combination of drugs, including samples generated from relapsed leukaemias, which are very difficult to treat using conventional chemotherapy. This work suggests novel opportunities for new leukaemia therapies.REC name
East Midlands - Leicester South Research Ethics Committee
REC reference
14/EM/0134
Date of REC Opinion
13 May 2014
REC opinion
Further Information Favourable Opinion