Childhood cancer: improving care through research

Céline Giustranti
Understanding the mechanisms of the development of childhood cancer is essential to curing more children while limiting side effects to a minimum. This is the goal of research into childhood cancers, which are different from adult cancers.
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They have some specific features:

  • They develop from embryonic tissue, in developing organs or tissues, whereas adults cancers occur mainly in tissue that is renewing or ageing.
  • The same tumor may have multi-tissue components.
  • The impact of childhood exposure to environmental mutagen factors is limited, and, in most cases, the role of genetic instability is probably also limited.
  • These cancers progress very quickly, in just a few weeks or sometimes days, which is not an indicator of their severity.
  •  Tumors in children are relatively “simple” from a genetic standpoint. The cells are younger and have undergone fewer alterations caused by the environment.

It is therefore essential to develop basic research geared specifically toward pediatric cancers. Only when their development mechanisms are thoroughly understood can care be improved.

Research in pediatric oncology, whether basic, translational or clinical, has three main objectives:

  • Finding new therapeutic options by targeting cancer cells or their environment, in particular using immunotherapy.
  • Developing more specific therapies to reduce side effects and recurrence.
  • Defining the risks associated with each tumor better.

Pediatric research: a historic mainstay at Institut Curie

Since the department was created in 1977, research has been conducted at Institut Curie to improve the understanding of pediatric tumors. Olivier Delattre’s team has contributed significantly to the understanding of the development mechanisms of some childhood tumors, and continues to work on the mechanisms at play in three pediatric cancers.

- Ewing tumors are a form of bone sarcoma that affects growing adolescents. A few years ago, Olivier Delattre’s team identified the genetic alteration that causes this pediatric cancer. It is a translocation occurring, in 85% of cases, between chromosomes 11 and 22, causing synthesis of an abnormal EWS-FLI-1 protein. Research on this genetic alteration is now used to establish diagnosis of Ewing tumors. Today the team is seeking to understand how the protein acts alone or in combination with two other genetic alterations more recently discovered in this same laboratory, and which characterize very aggressive forms of Ewing sarcoma. Research is continuing in order to characterize the normal cell that causes these cancers and to better understand why the occurrence of these tumors varies according to human populations.

- Neuroblastoma is a tumor of the sympathetic nervous system in children. Some tumors will progress, whereas others, including those that have metastasized, will shrink on their own, and we don’t know why. Two hypotheses are currently being explored: the immune response of the body, which manages to rid itself of the tumor, or an intrinsic feature of the tumor. In 2008, the identification of activating mutations of the ALK gene in some sporadic and familial neuroblastomas was a major breakthrough in understanding the disease and paved the way to potential targeted treatments. Two mutations that keep the ALK receptor permanently activated are frequently observed. Researchers have developed mouse models, each carrying one of the two mutations, to study their role during embryonic development and in the occurrence of cancers.

- Rhabdoid tumors are aggressive tumors that develop in very young children. They occur due to a single mutation responsible for inactivating the Smarcb1 gene, discovered by Olivier Delattre’s laboratory in 1998, which makes it a “simple” cancer model. The Smarcb1 protein regulates the compaction of certain regions of the genome, and this allows certain genes to be read or not. If it is absent, the genome remains compact and the cells remain at a stage close to that of stem cells. Using a mouse model, research continues to try to decipher the mechanisms responsible.

Pediatric oncology research has been strengthened recently with the arrival of Olivier Ayrault and his team. They are studying medulloblastoma, a tumor that develops in the cerebellum of young children. For example, they have uncovered the role of the Atoh1 and Huwe1 proteins in its occurrence, which offers up new therapeutic options to counteract their effect in the development of this tumor. At the same time, they are developing new proteomic approaches to better characterize the different types of medulloblastoma.

The researcher Célio Pouponnot is coordinating a PIC3i program whose goal is to find new ways of improving the effectiveness of radiotherapy in young children with brain tumors. This program involves exploring the feasibility of two approaches currently being developed by teams from Institut Curie to reduce side effects and to increase the efficacy of radiotherapy.

Concerning retinoblastoma, an eye tumor with a 99% survival rate in western countries, research is focusing on the development of less harmful treatments such as photo-sensitization. Chemists at Institut Curie are working to develop photosensitive molecules, known as photosensitizers, that can be activated by visible light.

Today, thanks to discoveries from research over the past four decades, 8 out of 10 children recover. However, cancer remains the second most-common cause of death for children aged under 15, with accidents in first place. Research must continue in order to improve the prognosis for pediatric cancers, to limit the consequences and to find new treatments.