Abstract
Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.
Highlights
Sarcomas are a heterogeneous group of malignancies of mesenchymal origin
Nintedanib is active against vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) [76] and its activity has been explored in a phase II trial randomizing advanced unselected soft-tissue sarcomas (STS) patients to receive ifosfamide or nintedanib as second-line therapy
No responses were observed in this study and there was no apparent relationship between best tumor response and the presence of FGF2 and FGFR1 protein overexpression or FGFR1 gene amplification [93]
Summary
Sarcomas are a heterogeneous group of malignancies of mesenchymal origin. In the last World Health Organization Classification of Soft Tissue and Bone Tumors [1], more than 100 different histologically and/or molecularly characterized mesenchymal tumors were described, the majority of which are soft-tissue sarcomas (STS). In the pediatric and young adult population, the incidence of cancer is significantly lower; STS are relatively more frequent, representing between 7–10% of all malignancies [3] In this age group, the most common histologies are rhabdomyosarcoma (RMS) and synovial sarcoma [3]. 5/38 (10.5%) quadruple wild-type GIST had FGFR1 alterations In another series of quadruple wild-type GIST, focal duplication of band 11q13.3 (involving FGF3/FGF4) was identified in 6/8 patients and this event was associated with the overexpression of FGF4, one of the most important ligands of FGFR1 [11] (Figure 1B). A gain in FGFR2 has been suggested as an additional potential mechanism associated with imatinib resistance [30]
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