News

Towards a new targeted therapy for pediatric cancers

03/07/2019

In Belgium, there are 70 000 new cases of cancer per year in adults, compared with 350 in children. Because of the lack of interest from pharmaceutical groups, treatments for pediatric cancers are developing much less rapidly than those for adults. The chemotherapy recommended in most childhood cancers is just as toxic as it was 20 years ago. In addition, this type of treatment has significant consequences for the child: infertility, deafness, and premature aging of the body. After chemotherapy sessions, children see their reservoir of stem cells decrease, thus impacting on the potential of proliferation and renewal of tissues.

For almost 15 years, Anabelle Decottignies, professor at UCLouvain's de Duve Institute, and her team, have been studying telomeres, these little structures at the end of chromosomes that play a crucial role in the cellular aging. In a normal cell, the more the telomeres wear out, the more our cells and organs age. It's natural aging. Conversely, in a cancer cell, the telomeres become unable to shorten. As a result, cancer cells do not age and divide indefinitely, forming tumors and metastases.

The goal of the UCLouvain researcher? Target the cancer cell to save the rest of the body through targeted therapy. The idea? Target the telomeres of the cancer cells to force them to age and, as a result, prevent them from dividing. To this end, it was necessary to understand the mechanisms that allow cancer cells to keep their eternal youth:

• In some cases, cancer cells reactivate the expression of an embryonic gene (90% of cancers): during the first stage of embryonic development, our cells have an indefinite proliferation potential thanks to an enzyme called telomerase. In 90% of cancers, this enzyme wakes up, forming tumors and metastases.

• In other cases, the cancer cells set up an alternative system (5 to 10% of cancers): this mechanism, called ALT (Alternative Lengthening of Telomeres), is set up especially in children’s tumors. The interest, from a therapeutic point of view, is that it is completely pathological, being inactive in all our healthy cells, making it an ideal target for new anti-tumor therapies.

Recently, and thanks mainly to the Télévie, the UCLouvain team has identified a protein that allows the survival of cancer cells that use the ALT mechanism, while the same protein is not essential for the survival of healthy cells. Its name: TSPYL5. This protein is absolutely essential to maintain the functionality of telomeres from cancer cells that have activated the ALT mechanism, but not the telomeres of cells using telomerase or the telomeres of healthy normal cells. When the TSPYL5 protein is removed, the ALT cancer cells die due to dysfunction of their telomeres. "This is the first time we have found a specific target to fight cancer cells in children", says Anabelle Decottignies.

For the past year, Anabelle Decottignies has been working with two other research teams to find new therapeutic molecules targeting TSPYL5:

• Joris Messens, Professor at the Center for Structural Biology at VUB. Their job? Identify molecules at the heart of the new therapy.

• Benjamin Elias, chemist, professor at UCLouvain's Institute of Condensed Matter and Nanosciences. Their asset? Synthesize the therapeutic molecules for ALT cancers.

What comes next? They will test these molecules in culture and verify that in vitro, they specifically kill ALT cancer cells, sparing healthy cells. After, preclinical tests will be performed in the mouse. And finally, clinical trials in pediatric oncology will take place. But it's not time yet. The first big challenge is to find those molecules that kill only cancer cells and not the others. The second will be to have very effective molecules that do not generate resistance from the cancer cell. If all these conditions are met, Anabelle Decottignies' team will have contributed to the improvement of treatments for pediatric cancers.

More details about this discovery in ScienceToday

Article describing this research

TSPYL5 Depletion Induces Specific Death of ALT Cells through USP7-Dependent Proteasomal Degradation of POT1
Harikleia Episkopou, Aurélie Diman, Eloïse Claude, Nikenza Viceconte, Anabelle Decottignies
Molecular Cell (2019) 75(3):469-482.E6

Financing

Télévie, FNRS, Foundation against Cancer, Fondation Roi Baudouin

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