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Origin of rare children cancer MRT discovered by Wellcome Sanger Institute, along with two potential treatments

The first proof of the origin of a rare and aggressive childhood cancer has been uncovered by Wellcome Sanger Institute researchers and their collaborators, along with two potential treatments.

Only four to five cases of malignant rhabdoid tumour (MRT) are recorded each year in the UK. It is one of the childhood cancers with the poorest outcomes, with no reliably effective treatment.

Dr Sam Behjati. Picture: Wellcome Sanger Institute
Dr Sam Behjati. Picture: Wellcome Sanger Institute

The rarity of MRT, and its aggressive nature, has made clinical trials exceptionally difficult and its origin has remained unknown until now.

A soft tissue cancer, it predominantly affects infants. While these tumours can arise in any part of the body, they typically form in the kidney and brain.

Sanger scientists, working with the Princess Máxima Center for Pediatric Oncology in the Netherlands, and collaborators, found MRT arises from developmental cells in the neural crest whose maturation is blocked by a genetic defect.

Two drugs that could be used to overcome the block and resume normal development were also identified.

Dr Sam Behjati, co-lead author of the study from the Wellcome Sanger Institute, said: “We began our inquiry into the origins of malignant rhabdoid tumours in late 2019, so we have gone from hypothesis to discovery of origin to possible treatments for the disease in just over a year.

“This was possible due to all the leading-edge tools available to us, from organoid technology to single-cell mRNA sequencing to drug screen databases.

“I hope this study will serve as the blueprint for discovering the origin of other childhood cancers and, ultimately, lead to better outcomes for children affected by these awful diseases.”

Sanger scientists carried out whole genome sequencing on two cases of MRT, alongside corresponding normal tissues. Phylogenetic analyses of the somatic mutations in the diseased and healthy tissue were then performed to ‘reconstruct’ the timeline of normal and abnormal development.

This showed MRT develops from progenitor cells on their way to becoming Schwann cells - a cell type found in the temporary group of stem cells known as the neural crest - due to a mutation in the SMARCB1 gene.

The mutation blocked the normal development of these cells, which can then go on to form MRT.

Researchers at the Princess Máxima Center inserted the intact SMARCB1 gene into MRT organoids - artificial tumours grown in the laboratory from the patients’ original tumours.

This successfully overcame the maturation block..

Single-cell mRNA analyses and predictions from these experiments enabled two existing medicines to be identified that overcome the maturation block.

Dr Jarno Drost, co-lead author of the study from the Princess Máxima Center for Pediatric Oncology, said: “To be able to identify where malignant rhabdoid tumour (MRT) comes from for the first time is an important step in being able to treat this disease, but to confirm that it is possible to overcome the genetic flaw that can cause these tumours is incredibly exciting. The fact that two drugs already exist that we think can be used to treat the disease gives us hope that we can improve outcomes for children diagnosed with MRT.”

Professor Richard Grundy, chair of the Children’s Cancer and Leukaemia Group, said: “It is fantastic to see this collaborative research bearing highly translatable outcomes in a childhood cancer with a currently poor prognosis.

“It emphasises the significant benefit of a National Tumour banking system, that allows collection of rarer tumours and in turn, the best use of such precious tissue through agreement of the CCLG Biological Studies committee that oversees this resource.

“For this to result in such a meaningful outcome gives new hope to children with malignant rhabdoid tumour (MRT).”

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