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Researching potential new treatments for childhood leukaemia

Advances in modern intensive chemotherapy, and identifying different levels of risk, have revolutionised the treatment of children with leukaemia. But resistant leukaemia subtypes and late effects of chemotherapy and relapses remain significant problems, and leukaemia still causes 30% of cancer deaths in children. We particularly need new, targeted treatments for treating children who have relapsed following earlier treatment.

Those with relapsed/refractory disease are currently treated with allogeneic stem cell transplants. This treatment is prolonged, intensive and toxic, and causes short and long-term side effects for the child. This places a significant burden on children and their families, both whilst the child is being treated and in terms of the supportive care, and can involve long stays in hospital.

There is a desperate need for new, targeted, more effective and less toxic treatments to help save the lives of more children, and provide better quality of life for the survivors. Dr Katherine Clesham (pictured below) and her team are looking for new, targeted treatments.

Project Details

  • Project Title

    Targeting c-MYB in acute leukaemia through drug repositioning

  • Lead Researcher

    Dr Katherine Clesham

  • Research Centre

    UCL Institute of Child Health

  • City & Institution Postcode

    London, WC1N 1EH

  • Start Date

    1 March 2017

  • Duration

    --

  • Grant Amount

    £250,000

Overview

We now know a great deal about leukaemia in childhood and survival rates have improved dramatically. But there are types which resist treatment, and leukaemia still causes 30% of cancer deaths in children.

Dr Katherine Clesham is looking for new, targeted treatments, particularly for those children who have relapsed following earlier treatment.

In her host laboratory, Dr Clesham has developed experimental leukaemia models and used them to carry out research aimed at identifying drugs that could be used to treat the disease.

She and her colleagues have found that the protein c-MYB is a central player in acute leukaemia, required for its development and maintenance. This suggests that targeting c-MYB function represents an exciting opportunity for new therapies.

Their analysis predicted that several microtubule destabilising agents (MDA) would interfere with c-MYB function, including a substance called vincristine.

As part of their laboratory work, the team also highlighted a drug called withaferin A (WfA), which is found in medicinal extracts of the Indian ginseng plant (Withania somnifera), used in traditional medicine and dietary supplements, and known to have some anti-leukaemia effects.

Dr Clesham found that WfA causes c-MYB to degrade and exhibits potent anti-leukaemia activity in vitro (in test tubes), reducing cell viability and colony forming activity.

In this project, she will continue her essential work by looking at how c-MYB contributes to the anti-leukaemia properties of WfA and vincristine, and whether this could be used as part of developing new treatments.

Potential impact

Dr Clesham predicts that this research will determine how effective the anti-leukaemia activity of WfA will be, and how valuable it could be when combined with vinka-alkaloid leukaemia therapy and treatment for different types of hard-to-treat leukaemia.

She then hopes that this knowledge can be used in future clinical research to develop it for use in new therapies to treat children with leukaemia.

There are also studies which suggest that this research might also help to develop new treatments for solid cancers such as paediatric low-grade gliomas, a class of brain tumours, so it is possible that the therapeutic impact of this project will not be limited to leukaemia.

About the research team

Dr Katherine Clesham is a senior haematology registrar and a clinical research associate in Dr Owen Williams’ group at ICH with invaluable experience of understanding molecular modelling of leukaemia. To carry out the current project, Dr Clesham has been awarded a Children with Cancer UK Clinical PhD Studentship.

Dr Williams will be supervising the project, which will also benefit significantly from ongoing collaborations with:

  • Dr Jasper de Boer, from the Cancer Section, UCL, a close collaborator on several drug repositioning projects;
  • Dr Philip Ancliff and Dr Sujith Samarasinghe, senior GOSH Haematology consultants who will ensure continuing access to paediatric leukaemia samples and provide insight into the clinical potential of this work;
  • Prof Marry M. van den Heuvel-Eibrink and Prof C. Michel Zwaan, Erasmus MC – Sophia Children’s Hospital, Rotterdam, existing collaborators who have provided paediatric AML samples and cell lines, and;
  • collaborations with Dr Olaf Heidenreich, Northern Institute for Cancer Research, Newcastle University and Dr Dominique Bonnet, The Francis Crick Institute.

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