Abstract
TARGETING SARCOMA METASTASIS BY THERAPEUTIC REWIRING OF THE MICROENVIRONMENT
ESMO Rare Cancers, Vol.4, 100064
12/2025
DOI: 10.1016/j.esmorc.2025.100064
Abstract
Objective
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, collagen-rich sarcomas. Over 50% of MPNSTs metastasize to the lungs, but there is no targeted treatment for metastatic MPNST patients. Two-thirds of MPNSTs have loss-of-function mutations in the histone methyltransferase Polycomb Repressive Complex 2 (PRC2), a master epigenetic regulator. Using time-lapse microscopy and orthotopic mouse models, we have shown that PRC2 loss drives MPNST metastasis through enzymatic remodeling of the extracellular matrix (ECM). In patient samples, PRC2 loss correlates with metastasis, increased fibrosis, and reduced survival. We identified lysyl oxidases (LOXs), a family of ECM remodeling enzymes, as key downstream effectors of PRC2 loss. This study investigates the mechanisms of LOX-driven metastasis and evaluates newly available LOX inhibitors currently in clinical trials.
Methods
Using robust preclinical models, we tested two LOX inhibitors that are well-tolerated in patients: PXS-5505 (pan-LOX) and PXS-5382 (LOXL2-specific). We assessed matrix-mediated invasion, metastatic progression, and tumor viability through in vitro assays and orthotopic mouse models. Fluorescently labeled tumor cells were used to monitor circulating tumor cells (CTC) and remodeling of the premetastatic niche.
Results
Both LOX inhibitors suppress matrix-dependent invasion in vitro, which is primarily mediated by extracellular LOXL2 activity. Preclinical studies show that treatment with either agent significantly extends survival and reduces lung metastases with limited toxicity. Ongoing work is defining the impact on tumor dissemination and immune landscape.
Conclusion
We identify PRC2-regulated ECM remodeling and epigenetic signaling as critical drivers of MPNST metastasis. Targeting LOX enzymes offers a promising therapeutic strategy, particularly in PRC2-deficient tumors. These findings provide strong rationale for clinical evaluation of LOX inhibitors in MPNST and other epigenetically dysregulated sarcomas.
Details
- Title: Subtitle
- TARGETING SARCOMA METASTASIS BY THERAPEUTIC REWIRING OF THE MICROENVIRONMENT
- Creators
- Rebecca Dodd - University of IowaAlexa Sheehan - University of IowaNina Carnevale - University of IowaGavin McGivney - University of IowaAkshaya Warrier - University of IowaJen Woods - University of IowaAshley Nelson - University of IowaNathan Steimel - University of IowaSai Teja Meka - University of IowaRachel Gasser - University of IowaCorinne Lambrecht - University of IowaAlyson Skala - University of Iowa
- Resource Type
- Abstract
- Publication Details
- ESMO Rare Cancers, Vol.4, 100064
- DOI
- 10.1016/j.esmorc.2025.100064
- ISSN
- 3050-4619
- Publisher
- Elsevier Ltd
- Language
- English
- Date published
- 12/2025
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9985093883102771
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