Exploring new targets for the treatment of ALT positive childhood cancers

29 January 2016

Dr David Clynes, Weatherall Institute of Molecular Medicine, University of Oxford

David was awarded a Paul O’Gorman Research Fellowship in 2015 to support a programme of research that aims to uncover new ways of treating certain childhood cancers known as ALT positive cancers. These include some devastating forms of childhood brain tumours.

His work has the potential to uncover the Achilles heel of ALT cancers, allowing for the identification and/or rational design of new tailored drugs.

Background – achieving immortality

David ClynesCancer occurs through the uncontrolled growth and division of cells, which eventually leads to the development of a tumour.

The number of times that a cell can divide is limited by the length of sequences of DNA called telomeres that are found at the end of chromosomes. In normal cells, telomeres shorten with every cell division. In cancerous cells, telomeres no longer shorten with cell divisions, meaning that the cell becomes immortal, continuing to grow and divide.

In some cancers, including some childhood cancers, the cells accomplish this by copying telomeres from the end of one chromosome to another. These cancers are called ALT (alternative lengthening telomere) positive cancers and include the incurable brain tumour Diffuse Intrinsic Pontine Glioma (DIPG).

Recent research has provided important clues as to how this lengthening process is activated in ALT cancers. David and colleagues have shown how a protein ATRX is involved in the suppression of telomere lengthening in normal cells. This protein is inactivated in most ALT cancers.

Understanding more about how ATRX works could provide insight into a new way of targeting the mechanisms underlying the process by which telomeres are copied (the so-called ALT pathway) and may provide a much-needed new approach to treating ALT positive cancers.

How to identify new cancer drugs

The challenge of identifying new cancer drugs can be approached in different ways.

One way is to understand which genes and proteins underpin an abnormal characteristic of a cancerous cell and use these as ‘targets’ for the design of new drugs. To this end, David will explore the relationship between ATRX and the abnormal characteristic of telomere lengthening. He will also use specialist technology to explore the effect of introducing mutations within a cell’s DNA sequence, in order to identify other proteins involved in the activation of the ALT pathway.

Another way to identify new cancer drugs is to screen pre-existing drugs and test them for their ability to limit the growth of, or preferentially kill, cancer cells. David will screen re-purposed drug libraries to identify pre-existing compounds that could be useful in the treatment of ALT positive cancers.

About David

David was our top graduate in 2004 and since then, he has been successfully awarded his DPhil from the University of Oxford and has carried out impressive graduate and postdoctoral research in some of the top epigenetics labs in the UK.
Professor David R Westhead, Head of School of Molecular and Cellular Biology, University of Leeds
Through our Fellowships, we aim to support outstanding young scientists in the development of a career in childhood cancer research.

We seek to identify ‘research leaders of the future’ and provide them with the support they need to achieve their full potential, making sure their talents are retained within the childhood cancer field.

David was awarded his Fellowship in 2015, out of our second round of Fellowship awards.

Having completed his DPhil (PhD) in Biochemistry at the University of Oxford, David spent six years at the prestigious Weatherall Institute of Molecular Medicine under Professors Richard Gibbons and Doug Higgs. His work on ALT positive cancers established a new line of research there, which he will now take forward with this Fellowship.

What difference will this work make?

Many forms of cancers that affect children are classified as ALT positive cancers. These include paediatric Glioblastoma Multiforme (GBM) and Diffuse Intrinsic Pontine Glioma (DIPG), two forms of brain tumour that have a particularly dismal prognosis.

A fresh approach is needed to develop new therapeutic strategies to beat these devastating diseases.

David’s work has great potential to uncover the Achilles heel of ALT cancers. This in turn will allow for the identification and/or rational design of new tailored drugs.

Interest in ALT cancers is extremely high in the scientific community, making this a very timely programme of work. Beyond its five-year term, this fellowship will provide the basis for the longer-term development and validation of new cancer therapies.

Read more: Brain and spinal tumours


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