Today, cancer research is advancing by leaps and bounds for adults. Not so for children, whose cancers are much rarer. Anabelle Decottignies and her team at the de Duve Institute have found a potential target that would kill cancer cells without harming other cells. They have just published their findings in the prestigious journal Molecular Cell, and are already tackling the search for molecules to use in a potential targeted therapy.
Curing cancer in all children
Have you heard of KickCancer? In recent months, the singer Angèle has talked about this foundation whose mission is ambitious to say the least: curing cancer in all children. Today, few of us know that most cancer research is related to adults, as are the majority of innovations to treat malignant tumours. Too few target children. Why? ‘Paediatric cancers are rare’, says Anabelle Decottignies, an FNRS researcher and head of a research team at the de Duve Institute. ‘In Belgium, there are 70,000 new cases of cancer every year in adults, against 350 in children. Of course pharmaceutical companies aren’t interested in the latter.’
Excessively toxic chemotherapy
Due to lack of research, treatments for paediatric cancers have not evolved. The chemotherapy recommended for most childhood cancers is just as toxic as it was 20 years ago. In addition, the treatment has significant short, medium and long-term consequences. Studies have shown that chemotherapy in children can lead to infertility and deafness. More generally, the treatment makes the body age prematurely. After chemotherapy sessions, the child suffers a loss of stem cells, which are crucial to the healing and regeneration of its tissues. The capacity of tissues to regenerate therefore diminishes, yet the cured child still has many years ahead of him.
Eternal telomeres
Dr Decottignies’s laboratory has decided to buck the trend and conduct research on paediatric cancers. As we explained it in a previous article, for 15 years Dr Decottignies has studied telomeres, the little bits of chromosomes that play a vital role in ageing. In a normal cell, as telomeres wear out, cells and organs age. This is natural ageing. Conversely, in a cancer cell, telomeres don’t wear out. As a result, the cancer cells don’t age and they divide indefinitely, forming tumours and metastases. The discovery of telomeres and telomerase, the enzyme that ensures the longevity of these telomeres, was rewarded with the 2009 Nobel Prize in Medicine.
Two mechanisms of eternal youth
Gradually, scientists have come around to the idea of trying to target cancer cell telomeres to force them to age and thus prevent them from dividing. To do so, it was necessary to understand the mechanisms that allowed cancer cells to keep their youth eternal:
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On the one hand, cancer cells reactivate the expression of an embryonic gene (90% of cancers): in the early stage of embryonic development, our cells are ‘eternally young’. This immortality is triggered by telomerase, an enzyme that maintains telomere size. In 90% of cancers, this enzyme can awaken, generating infinite divisions and forming tumours and metastases.
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On the other hand, cancer cells set up an alternative system (5 to 10% of cancers): this mechanism, called alternative lengthening of telomeres (ALT), is not present in any of our normal cells and is quite characteristic in certain cancers, especially paediatric cancers such as brain cancers, bone cancers or cancers specific to the child. It’s also found in some adult cancers, including sarcomas.
Targeting telomeres
Given the ALT mechanism isn’t present in healthy cells, if we succeed in targeting the cancer cell, the treatment will save the rest of the body. Thus targeted therapy is needed. However, currently, the preferred treatments in children are non-specific chemotherapies that attack stem cells and have long-term adverse effects. Recently, the team identified a target (a gene) that could allow to kill the ALT cell without killing the other cells. Its name: TSPYL5. ‘This is the first time that we have found a specific target for cancer cells with an ALT telomere maintenance mechanism’, Dr Decottignies says.
Prevent interaction between two proteins
Dr Decottignies and her team have deepened the involvement of the TSPYL5 gene in the alternative mechanism. They have just published their findings in the prestigious journal Molecular Cell. The TSPYL5 gene codes for the TSPYL5 protein which blocks, by way of binding to it, another protein called USP7. However, if the TSPYL5 protein is removed, USP7 becomes able to act and cause cell death. Thanks to funding from the Cancer Foundation and in collaboration with VUB and UCLouvain, Dr Decottignies will look for molecules capable of preventing the interaction between the USP7 protein and TSPYL5. The USP7 protein can thus kill the cancer cell and prevent the development of a tumour or metastasis.
How to find these molecules?
Since last year, the strategy for finding this molecule has been clarified. From now on, Dr Decottignies’s team can count on two collaborations:
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Prof. Joris Messens of the VIB-VUB Center for Structural Biology, Brussels: The VUB team will help identify these molecules. They are figuring out how the two proteins (USP7 and TSPYL5) work together. Then they will use two approaches:
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through crystallography, they intend to find molecules that prevent the interaction between these two proteins;
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they will focus on ‘nanobodies’, proteins that are the smallest functional entity of the antibody and can enter certain cells, as long as they are small and thus prevent the interaction between the targeted proteins.
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Prof. Benjamin Elias, Institute of Condensed Matter and Nanosciences, UCLouvain: His group of chemists will help Dr Decottignies's team synthesise therapeutic molecules for ALT cancers.
Searching for the right molecules
Dr Decottignies has started collaboration with VUB to identify new molecules that will target the interaction. To validate them, they will be placed in culture and verified in vitro that they kill ALT cells specifically and spare healthy cells. Next, preclinical tests will be done in mice from xenografts, that is, human tumour cells injected into immunodeficient mice. Finally, clinical trials can take place. The first big challenge is to find molecules that kill only cancer cells. The second will be to have very effective molecules that don’t induce resistance from the cancer cell. If all these conditions are met, Dr Decottignies’s team will have significantly contributed to the improvement of treatments for paediatric cancers. She has also been actively involved in the KickCancer Foundation's mission to cure cancer in all children.
Lauranne Garitte
A glance at Anabelle Decottignies' bio
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A UCLouvain bioengineering graduate, Anabelle Decottignies completed her PhD, on drug resistance mechanisms (yeast as a model organism), in the UCLouvain Faculty of Agronomy from 1992 to 1998. She then pursued a three-year postdoc on the study of cell cycle regulators in Paul Nurse's laboratory in London. In 2001, she became an FNRS postdoc researcher at UCLouvain and the de Duve Institute, in 2004 an FNRS research associate, and in 2014 an FNRS senior research associate. She received the King Baudouin Foundation’s Simon Bauvin, Christian Lispet, Robert Brancart and Denise Raes Fund Award in 2016, became Officier du Mérite wallon in the science category in 2017, and received the Allard-Janssens Award in May 2018. |