Childhood Cancer: A Promising New Approach to Immunotherapy | Newsroom

In the presence of the transcription factor EWSR1-FLI-1 (left), the (green) transcript of the NG3 gene – specific for Ewing’s sarcoma – is abundant. When EWSR1-FLI-1 is lowered (right), the NG3 transcript disappears completely. A replica of the FXR1 gene (red) – not dependent on EWSR1-FLI-1 – is present. Kyra Bergman, Antoine Cullen

Immunotherapy has been on the rise in recent years, as benefits for patients are important and research in progress is promising. However, this method often remains ineffective in the fight against childhood cancer. Scientists at Institut Curie, Inserm and CNRS have just demonstrated a new activity in Ewing’s sarcoma-induced transcription factor.[1] : It induces the expression of highly tumor-specific genes. A discovery that could pave the way for immunotherapy in sarcomas and more widely in pediatric tumors. These results were published in the journal May 11, 2022 Molecular cells, In support of the National Cancer League.

Immunotherapy is increasingly being used to treat cancer because of its significant benefits to patients. This treatment is characterized by high efficiency and longevity by maintaining the response of the immune system over time. Many promising studies are currently being conducted. However, immunotherapy has one major limitation. It remains largely ineffective in the treatment of pediatric cancer. In fact, this therapeutic approach is based on a basic concept: tumor-specific genetic mutations can be identified as non-self by the immune system. However, in childhood cancer, these mutations are rare. A study conducted by the team of Dr. Olivier Delattre, Chief Insom Research Director of the Cancer, Variation, Instability and Plasticity Unit (CHIP – Institut Curie / Inserm / University of Paris) highlighted only the expression of highly specific genes. Ewing’s sarcoma1And more widely in specific pediatric sarcomas and tumors.

The genetic mutations of sarcomas exhibit fancy activity

Many cancers are characterized by a special genetic mutation called “gene fusion” that results in the release of oncogenic proteins (transcription factors). About 95% of Ewing tumors are due to a characteristic genetic fusion: in most cases it is a transplant[2] Which occurs between chromosomes 11 and 22 and results in an abnormal protein synthesis, transcription factor EWS-FLI-1. Fusions between the two genes are found in a large number of sarcomas, resulting in the presence of these special transcription factors called “chimeric”[3] Oncogenes “.

In the wake of this first discovery, the Institute is taking another step towards understanding the important role of EWS-FLI-1 in childhood tumor diversity and plasticity team led by Dr. Delatt. Researchers have shown that this Ewing sarcoma-specific transcription factor induces the expression of a set of genes in a region of the genome that is usually “silent”, in other words, not replicated. Their results indicate that these “neogenes” may be translated into highly specific peptides because they are highly expressed in Ewing’s sarcoma cells, where they are absent from the body’s normal cells.

The role of these transcription factors in metastatic processes is already known, but this is the first time such activity has been observed.

“The existence of this particular genetic mutation is found in many pediatric cancers, thus increasing the likelihood of immunotherapy targeting these tumor-specific proteins. This discovery could prove revolutionary for the management of childhood tumors, the second leading cause of death in children under 15 today.” Cancer, heterogeneity, instability and plasticity – explained by Dr. Olivier Delatre, Director of Insom Research, Chip (Institute Curie / INSERM / University of Paris) Unit. “We now need to show that these newly identified proteins can form real therapeutic targets for the development of immunotherapy. Conducted in collaboration with the Clinical Immunology Laboratory. Dr. Delatre finished.

More generally, study authors have shown that these hundreds of neogenes can be detected in a variety of cancers identified by oncogenic chimeric transcription factors. The high specificity and recurrence of these peptides in different types of childhood sarcoma make them a promising therapeutic target for the development of immunotherapy in the treatment of cancer in their children.

Treatment of pediatric cancer at the Institute Curie

Every year in France, about 2,200 new cases of pediatric cancer are diagnosed. If more than 80% of children survive five years after diagnosis, it is important to develop new therapeutic strategies for those who have not yet been cured, and to reduce the sequelae of conventional treatment. At Institute Curie, 300 to 400 young patients are cared for each year by a multidisciplinary team at the SIREDO Center (Care, Innovation, Research in Oncology for Children, Adolescents and Young Adults) run by Dr. Delatre. With the help of associations, they conduct basic, translational and clinical studies with a strong specialization in solid tumors: neuroblastoma, medulloblastoma, Ewing’s sarcoma, retinoblastoma and even certain brain tumors.

[1] The second most common malignant bone tumor after osteosarcoma in adolescents and young adults, Ewing’s sarcoma develops mainly in the bones of the pelvis, ribs, femur, fibula, and tibias. Through its strong invasiveness, Ewing’s sarcoma can cause other cancerous foci to appear on the body, especially in the lungs, skeleton, and bone marrow.

[2] Chromosomal rearrangement that involves the reciprocal exchange of chromosomal components between non-homologous chromosomes.

[3] When a single DNA sequence comes from multiple transcripts or parent sequences.

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