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Review
. 2025 Feb 12;26(4):1542.
doi: 10.3390/ijms26041542.

Chondrosarcoma: New Molecular Insights, Challenges in Near-Patient Preclinical Modeling, and Therapeutic Approaches

Affiliations
Review

Chondrosarcoma: New Molecular Insights, Challenges in Near-Patient Preclinical Modeling, and Therapeutic Approaches

Lorena Landuzzi et al. Int J Mol Sci. .

Abstract

Chondrosarcoma (CS), the second most common malignant bone tumor after osteosarcoma, accounts for 20-30% of all malignant bone tumors. It mainly affects adults, middle-aged, and elderly people. The CS family includes various entities displaying peculiar biological, genetic, and epigenetic characteristics and clinical behaviors. Conventional CS is the most common subtype. High-grade, dedifferentiated, and mesenchymal CS, as well as unresectable and metastatic CS, exhibit poor prognoses due to their intrinsic resistance to radiotherapy and chemotherapy, underscoring the urgent need for novel therapeutic strategies. CS research is dealing with several challenges. Experimental studies can rely on animal and patient-derived models, but the paucity of representative near-patient preclinical models has hampered predictive drug screening research. This review describes the main clinical and molecular features of CS subtypes, discussing recent data on the genetic alterations and molecular mechanisms involved in CS pathogenesis and progression. The review provides an overview of the current in vitro and in vivo CS models, discusses their advantages and limitations, and highlights the recent efforts in the development of new targeted therapies against CS dependencies, including IDH1/2 mutations, NAD+ dependency, and SIRT1-HIF-2α axis, or exploring DR5 targeting, antiangiogenic therapies, epigenetic drugs, and immunological approaches. All such strategies, in combination with advanced preclinical modeling and personalized multi-omic profiling, hold promise for improving the survival of patients with advanced CS.

Keywords: chondrosarcoma; immunotherapy; multi-omic profiling; preclinical models; targeted therapies.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
CS preclinical models. Experimental models that have been generated for CS can be distinguished into patient-derived models and animal models. Patient-derived models (upper panel) include cell lines, organoids and 3D cultures, embryonal models established using chorion-allantoic membranes, and xenograft models, both CDX and PDX, established using immunodeficient mice. Animal models (lower panel) range from spontaneous transplantable CS models of rats and hamsters to genetically modified transgenic or conditional mouse models carrying different combinations of genes involved in the pathogenesis of CS (Created in BioRender. K.S. (2025) https://BioRender.com/n24l231, accessed on 8 February 2025).

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