Characterising the proteomic landscape of ultra-rare soft tissue sarcomas
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Embargo End Date
2027-07-21
ICR Authors
Authors
Tam, YB
Document Type
Thesis or Dissertation
Date
2025-07-21
Date Accepted
Abstract
Ultra-rare soft tissue sarcomas (STS) are a group of 56 understudied, molecularly distinct STS histotypes that account for 20% of all STS cases. The current standard of care is largely a ‘one size fits all’ approach, with few targeted therapy options approved for specific ultra-rare STS histotypes. Due to the rarity of these cases, the biology of many of these histotypes are poorly understood and these patients are commonly under-represented in STS clinical trials. This has led to delays in the development of effective targeted therapies for these patients, leading to no improvement in prognosis in recent decades. To address this unmet need, I collated the largest known cohort of ultra-rare STS cases, consisting of 288 formalin-fixed paraffin embedded patient samples representing 14 ultra-rare STS histotypes. To better characterise the disease biology of ultra-rare STS, I performed comprehensive proteomic profiling by mass spectrometry to understand the similarities and differences between histotypes at protein level and pathway gene set level. New molecular subtypes of ultra-rare STS were identified based on proteomics and biological pathway data, giving insight to patients with similar disease biology. This may help identify patients that could benefit from basket trials, and the type of pathways that may be targetable for new treatments. Associations between protein and gene expression with other clinicopathological variables, such as anatomical site and patient age were also evaluated. This led to the identification of enriched pathways that were characteristic in patients with specific features, such as in adolescents and young adults, including markers that may be indicative of patient progression and outcomes. Heterogeneity within epithelioid sarcoma, an STS histotype that I have a larger number of cases for, will also be evaluated. Epithelioid sarcomas are known to have two distinct subtypes, distal and proximal, but little is known about their differences at a molecular level. Additionally, a heterogeneous response to targeted treatments has been observed across epithelioid sarcoma patients in the clinic, thus understanding intra-subtype molecular differences within this histotype will be essential to identify patients more likely to respond to standard of care and targeted therapies.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Mol and Systems Oncology