Preclinical Evaluation of Nintedanib, a Triple Angiokinase Inhibitor, in Soft-tissue Sarcoma: Potential Therapeutic Implication for Synovial Sarcoma

Abstract

Sarcomas are rare cancers that make up about 1% of all cancers in adults; however, they occur more commonly among children and young adolescents. Sarcomas are genetically complex and are often difficult to treat given the lack of clinical efficacy of any of the currently available therapies. Receptor tyrosine kinases (RTK) such as c-Kit, c-Met, PDGFR, IGF-1R, as well as FGFR have all been reported to be involved in driving tumor development and progression in adult and pediatric soft-tissue sarcoma. These driver kinases often act as critical determinants of tumor cell proliferation and targeting these signal transduction pathways remains an attractive therapeutic approach. Nintedanib, a potent triple angiokinase inhibitor, targets PDGFR, VEGFR, and FGFR pathways critical for tumor angiogenesis and vasculature. In this study, we evaluated the preclinical efficacy of nintedanib in soft-tissue sarcoma cell lines. Nintedanib treatment resulted in significant antiproliferative effect in cell lines with high expression of RTK drug targets. Furthermore, treatment with nintedanib showed significant downregulation of downstream phosphorylated AKT and ERK1/2. Finally, treatment with nintedanib resulted in significant tumor growth suppression in mouse xenograft model of synovial sarcoma. Notably, both the and efficacy of nintedanib was superior to that of imatinib, another multikinase inhibitor, previously tested with minimal success in clinical trials in sarcoma. Overall, the data from this study provide a strong rationale to warrant further clinical exploration of this drug in patients with synovial sarcoma..

Phospho-Protein Arrays as Effective Tools for Screening Possible Targets for Kinase Inhibitors and Their Use in Precision Pediatric Oncology

“…As described in our previous studies, the levels of phosphorylation were quantified using ImageJ software (15) and subsequently normalized to the positive control spots (18). Although the experimental use of a phospho-protein array is usually based on the comparison of acquired data with a reference cell line (18) or with untreated control cells (19), the employment of these arrays in clinical practice apparently requires a different approach.…”

Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours

“…2C ). Nintedanib potently inhibited the phosphorylation of KIT, such as Y703, Y719 and Y823, and downstream mediators, such as AKT and STAT3, which was also observed in cell lines with high expression RTK drug targets [ 35 ], in GIST‐T1 and GIST‐882 (imatinib sensitive) cells. Interestingly, in GIST‐5R (imatinib resistant) cells, nintedanib was more potent than sunitinib against KIT Y719 phosphorylation, which regulates SCF‐mediated cell migration [ 36 ], and both nintedanib and sunitinib displayed profound inhibitory effects on KIT Y703 and Y823 phosphorylation.…”

Inhibition of FGF‐FGFR and VEGF‐VEGFR signalling in cancer treatment

“…Nintedanib (BIBF1120) is a non‐selective FGFR TKI that competitively and reversibly blocks the ATP‐binding pocket of FGFR1‐3, VEGFR1‐3 and PDGFR 166 . This inhibitor has obtained promising results on different cancers in preclinical studies as a single agent or combination with standard chemotherapies, including lung, prostate, colorectal, pancreatic, ovarian cancer and STS 166‐168 . Based on these results, nintedanib has been or is being tried in various tumour types in clinical trials.…”