Scientists Map a Battle Plan Against One of Medicine’s Rarest and Deadliest Childhood Cancers

Desmoplastic small round cell tumour, or DSRCT, is one of the rarest and most unforgiving cancers in medicine. It strikes mainly adolescents and young adults, with an age-adjusted incidence of just 0.3 cases per million people, yet fewer than one in five patients survives beyond five years. Now, a landmark international workshop convened by the medical research charity LifeArc, together with the Innovative Therapies for Children and Adolescents with Cancer network, Cancer Research UK and the Cancer Grand Challenge PROTECT team, has produced the most detailed roadmap yet for developing new treatments against this devastating disease. The consensus document, published in the British Journal of Cancer, brings together oncologists, tumour biologists, drug developers and patient advocates from Europe, North America and South America in an unprecedented effort to break a three-decade-long therapeutic stalemate.

The scale of the challenge is sobering. DSRCT is an aggressive soft tissue sarcoma in which nests of small round tumour cells are embedded in a dense, fibrous stroma, the very desmoplastic tissue that gives the disease its name. In 90 per cent of patients, tumours have already spread diffusely throughout the abdominal cavity by the time of diagnosis, and half have metastasised beyond the peritoneum to the liver, lungs, lymph nodes or bones. Eighty per cent of cases occur in post-pubertal males, with a peak incidence between the ages of 20 and 24. Current treatment, a punishing combination of intensive multi-agent chemotherapy, cytoreductive surgery and whole-abdomen radiotherapy, has produced no meaningful improvement in survival in 30 years. Even after complete surgical resection, some studies report recurrence or progression in 84 per cent of patients, and up to 70 per cent of surgically treated patients require further procedures.

At the molecular level, DSRCT is a paradox. It is a genomically ‘quiet’ cancer, meaning it carries remarkably few mutations beyond its defining event: a reciprocal translocation between chromosomes 11 and 22 that fuses the EWSR1 gene to WT1, producing an abnormal transcription factor found exclusively in tumour cells. This fusion protein, present in every DSRCT cell, combines the transactivation domain of EWSR1 with the DNA-binding domain of WT1, rewiring gene expression across the genome. Laboratory studies have shown that suppressing the fusion protein halts tumour cell growth entirely, triggering cell-cycle arrest and shrinking xenograft tumours in mice. The workshop participants unanimously ranked EWSR1::WT1 as the highest-priority target, but hitting it directly is extraordinarily difficult because the protein is structurally disordered and buried in the cell nucleus.

One of the most exciting strategies discussed targets the fusion protein through the immune system. The chromosomal breakpoint creates a unique junctional amino acid sequence, a neoantigen that exists only in tumour cells and never in healthy tissue. Using mass spectrometry of HLA molecules, researchers confirmed that this neopeptide is displayed on the cell surface by two globally common HLA variants, HLA-A03 and HLA-A11. Engineered T-cell receptors designed to recognise this peptide have shown complete and durable responses in animal models. The catch is HLA restriction: only around 32 per cent of DSRCT patients worldwide carry the required tissue types, though efforts are under way to broaden coverage, and future iterations may be armoured with immune-stimulating cytokines such as interleukin-18. A parallel technology, peptide-centric chimeric antigen receptors, which are not limited by HLA type, is earlier in development but could eventually offer a wider route to the same target.

Indirect approaches to disabling the fusion protein are already in the clinic. Trabectedin and its analogue lurbinectedin are small molecules that bind the DNA minor groove and disrupt the fusion protein’s activity, and lurbinectedin is now being tested in DSRCT both as a monotherapy and in combination with irinotecan. Beyond the fusion itself, the workshop identified several cell-surface proteins as promising targets, including LRRC15, the somatostatin receptors SSTR3 and SSTR5, NECTIN4, STEAP1 and mesothelin. Each is attractive in principle, but the participants stressed that proteomic validation in DSRCT tissue remains thin. A single case report of a patient with atypical DSRCT achieving a 23-month response to the NECTIN4-targeting antibody-drug conjugate enfortumab vedotin hints at what may be possible, but the panel cautioned that far more expression data are needed before such drugs can be justified for routine investigation.

Some of the most encouraging clinical signals come from drugs already approved for other cancers. Trastuzumab deruxtecan, an antibody-drug conjugate linking a HER2-targeting antibody to a topoisomerase I inhibitor, produced partial responses in nine of 17 DSRCT patients with measurable disease in a single-centre off-label study, with a further eight achieving stable disease. Strikingly, response did not correlate with HER2 expression levels, and preclinical work suggests the drug is active even at low HER2 abundance. Those results have propelled a biomarker-agnostic trial through the Children’s Oncology Group. Other trials now under way include an antibody-drug conjugate against claudin-6, the NTRK3 inhibitor repotrectinib combined with chemotherapy, and the somatostatin analogue pasireotide as maintenance therapy for tumours expressing SSTR2, 3 or 5.

The workshop also prioritised existing clinical assets that could be redeployed. B7-H3, a cell-surface protein expressed in up to 96 per cent of DSRCT tumours but minimally in healthy tissue, was rated a very high priority, with an antibody-drug conjugate carrying a topoisomerase 1 payload considered the optimal modality. Inhibitors of the DNA damage response also ranked highly, because DSRCT cells show high levels of replication stress; a phase I trial of the CHK1/2 inhibitor prexasertib with irinotecan produced partial responses in six of 19 patients. Androgen receptor signalling emerged as potentially ‘low-hanging fruit’, given that hundreds of AR-targeted drugs already exist for prostate cancer and that AR is highly expressed in many DSRCT cases, particularly in males. FGFR4, a direct transcriptional target of the fusion protein, and STEAP1 round out the shortlist, with cell-surface approaches such as CAR T-cells and antibody-drug conjugates favoured over small-molecule inhibitors.

Yet the workshop was candid about the barriers that have kept DSRCT patients waiting. With so few patients, pharmaceutical companies have little financial incentive to run trials, and regulatory frameworks designed for common adult cancers fit poorly. The participants proposed three complementary solutions: international platform trials such as the OCTOPUS master protocol for non-rhabdomyosarcoma soft tissue sarcomas, which can test multiple agents simultaneously and adapt as data emerge; the systematic collection of high-quality off-label and real-world evidence, as demonstrated by the trastuzumab deruxtecan experience; and the inclusion of DSRCT patients in adult trials of relevant targets, for example by adding signal-seeking DSRCT cohorts to prostate cancer studies of androgen receptor inhibitors. Trials in the setting of minimal residual disease, where the chance of altering the disease’s natural history may be greatest, were also flagged as a priority, alongside better tools to detect and characterise the residual cells that seed relapse.

For a disease that has defied progress for a generation, the workshop’s message is one of cautious momentum. The biology of DSRCT, once an impenetrable black box, now offers a defined driver, a tumour-specific neoantigen, a growing list of surface targets and a pipeline of drugs, many already tested in humans, that could be redirected toward these patients. The participants concluded that progress will come from a dual strategy: developing entirely new agents against the EWSR1::WT1 fusion while simultaneously evaluating existing therapeutics in well-designed, internationally harmonised trials that enrol children, adolescents and adults together. If the roadmap is followed, the first generation of DSRCT patients with genuine targeted options may not be far away, turning one of oncology’s most neglected diagnoses into a test case for how science can serve the rarest of the rare.

Subject of Research: Therapeutic target prioritisation and clinical trial strategy for desmoplastic small round cell tumour

Article Title: Paediatric therapeutic development workshop on desmoplastic small round cell tumours

Article References: Paediatric therapeutic development workshop on desmoplastic small round cell tumours. (n.d.). https://doi.org/10.1038/s41416-026-03631-7

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03631-7

Keywords: DSRCT, EWSR1::WT1 fusion, paediatric oncology, sarcoma, T-cell receptor therapy, antibody-drug conjugates, B7-H3, androgen receptor, DNA damage response, rare cancers, drug development, clinical trials