Probing the Effects of the FGFR-Inhibitor Derazantinib on Vascular Development in Zebrafish Embryos
TL;DR: In this article, the effect of derazantinib (DZB) on blood vessel morphogenesis was investigated and compared to known specific FGFR and VEGFR inhibitors, revealing a potential dual role for DZB as a potent anti-angiogenic treatment.
Abstract: Angiogenesis is a fundamental developmental process and a hallmark of cancer progression. Receptor tyrosine kinases (RTK) are targets for cancer therapy which may include their action as anti-angiogenic agents. Derazantinib (DZB) is an inhibitor of the fibroblast growth factor receptors (FGFRs) 1–3 as well as other kinase targets including vascular endothelial growth factor receptor 2 (VEGFR2), colony stimulating factor-1 receptor (CSF1R) and platelet-derived growth factor beta receptor (PDGFRbeta). This study aimed to investigate the effect of DZB on blood vessel morphogenesis and to compare its activity to known specific FGFR and VEGFR inhibitors. For this purpose, we used the developing vasculature in the zebrafish embryo as a model system for angiogenesis in vivo. We show that DZB interferes with multiple angiogenic processes that are linked to FGF and VEGF signalling, revealing a potential dual role for DZB as a potent anti-angiogenic treatment.
Citations
More filters
TL;DR: In this article, the clinical role of derazantinib in patients with intrahepatic cholangiocarcinoma (iCCA) harboring actionable oncogenic FGFR2 fusions/rearrangements, mutations and amplifications was evaluated.
Abstract: Introduction This review evaluates the clinical role of fibroblast growth factor receptor 2 (FGFR2) inhibition with derazantinib in patients with intrahepatic cholangiocarcinoma (iCCA) harboring actionable oncogenic FGFR2 fusions/rearrangements, mutations and amplifications. FGFR inhibitors such as derazantinib are currently being evaluated to address the unmet medical need of patients with previously treated, locally advanced or metastatic iCCA harboring such genetic aberrations. Areas covered We summarize the pharmacokinetics, and the emerging safety and efficacy data of the investigational FGFR inhibitor derazantinib. We discuss the future directions of this novel therapeutic agent for iCCA. Expert opinion Derazantinib is a potent FGFR1‒3 kinase inhibitor which also has activity against colony stimulating factor-1‒receptor (CSF1R) and vascular endothelial growth factor receptor‒2 (VEGFR2), suggesting a potentially differentiated role in the treatment of patients with iCCA. Derazantinib has shown clinically meaningful efficacy with durable objective responses, supporting the therapeutic potential of derazantinib in previously treated patients with iCCA harboring FGFR2 fusions/rearrangements. The clinical safety profile of derazantinib was well manageable and compared favorably to the FGFR inhibitor class, particularly with a low incidence of drug-related hand-foot syndrome, stomatitis, retinal and nail toxicity. These findings support the need for increased molecular profiling of cholangiocarcinoma patients.
8 citations
TL;DR: Derazantinib (DZB) is an inhibitor of fibroblast growth factor receptors 1-3 (FGFR1-3), with additional activity against colony-stimulating-factor-1 receptor (CSF1R) as discussed by the authors .
Abstract: Derazantinib (DZB) is an inhibitor of fibroblast growth factor receptors 1–3 (FGFR1–3), with additional activity against colony-stimulating-factor-1 receptor (CSF1R). We have profiled the activity of DZB in gastric cancer (GC) as monotherapy and combined with paclitaxel, and explored means of stratifying patients for treatment. The antiproliferative potency of DZB in vitro was quantified in 90 tumor cell lines and shown to correlate significantly with FGFR expression (<0.01) but not with FGFR DNA copy-number (CN) or FGFR mutations. In four GC cell lines in vitro, little or no synergy was observed with paclitaxel. In athymic nude mice, bearing cell-line derived xenografts (CDX) or patient-derived xenograft (PDX) GC models, DZB efficacy correlated highly significantly with FGFR gene expression (r2 = 0.58; P = 0.0003; n = 18), but not FGFR mutations or DNA-CN. In FGFR-driven GC models, DZB had comparable efficacy to three other FGFR inhibitors and was more efficacious than paclitaxel. DZB had dose-dependent plasma pharmacokinetics but showed low brain penetration at all doses. GC models (one CDX and six PDX) were tested for sensitivity to the combination of DZB and paclitaxel and characterized by immunohistochemistry. The combination showed synergy (5) or additivity (2), and no antagonism, with synergy significantly associated (P < 0.05) with higher levels of M2-type macrophages. The association of strong efficacy of the combination in vivo with M2 macrophages, which are known to express CSF1R, and the absence of synergy in vitro is consistent with the tumor microenvironment also being a factor in DZB efficacy and suggests additional means by which DZB could be stratified for cancer treatment in the clinic.
1 citations
TL;DR: Derazantinib (DZB) is an inhibitor of the fibroblast growth factor receptors 1-3 (FGFRi) with similar potency against colony-stimulating factor receptor-1 (CSF1R), a protein important in the recruitment and function of tumor-associated macrophages as discussed by the authors .
Abstract: Derazantinib (DZB) is an inhibitor of the fibroblast growth factor receptors 1–3 (FGFRi) with similar potency against colony-stimulating factor receptor-1 (CSF1R), a protein important in the recruitment and function of tumor-associated macrophages. DZB inhibited pCSF1R in the macrophage cell line RAW264.7, and tumor cells GDM-1 and DEL, and had the same potency in HeLa cells transiently over-expressing FGFR2. DZB exhibited similar potency against pCSF1R expressed by isolated murine macrophages, but as in the cell lines, specific FGFRi were without significant CSF1R activity. DZB inhibited growth of three tumor xenograft models with reported expression or amplification of CSF1R, whereas the specific FGFRi, pemigatinib, had no efficacy. In the FGFR-driven syngeneic breast tumor-model, 4T1, DZB was highly efficacious causing tumor stasis. A murine PD-L1 antibody was without efficacy in this model, but combined with DZB, increased efficacy against the primary tumor and further reduced liver, spine and lung metastases. Immunohistochemistry of primary 4T1 tumors showed that the combination favored an antitumor immune infiltrate by strongly increasing cytotoxic T, natural killer and T-helper cells. Similar modulation of the tumor microenvironment was observed in an FGFR-insensitive syngeneic bladder model, MBT-2. These data confirm CSF1R as an important oncology target for DZB and provide mechanistic insight for the ongoing clinical trials, in which DZB is combined with the PD-L1 antibody, atezolizumab.
References
More filters
TL;DR: A series of stages for development of the embryo of the zebrafish, Danio (Brachydanio) rerio is described, providing for flexibility and continued evolution of the staging series as the authors learn more about development in this species.
Abstract: We describe a series of stages for development of the embryo of the zebrafish, Danio (Brachydanio) rerio. We define seven broad periods of embryogenesis--the zygote, cleavage, blastula, gastrula, segmentation, pharyngula, and hatching periods. These divisions highlight the changing spectrum of major developmental processes that occur during the first 3 days after fertilization, and we review some of what is known about morphogenesis and other significant events that occur during each of the periods. Stages subdivide the periods. Stages are named, not numbered as in most other series, providing for flexibility and continued evolution of the staging series as we learn more about development in this species. The stages, and their names, are based on morphological features, generally readily identified by examination of the live embryo with the dissecting stereomicroscope. The descriptions also fully utilize the optical transparancy of the live embryo, which provides for visibility of even very deep structures when the embryo is examined with the compound microscope and Nomarski interference contrast illumination. Photomicrographs and composite camera lucida line drawings characterize the stages pictorially. Other figures chart the development of distinctive characters used as staging aid signposts.
10,612 citations
TL;DR: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions and is implicated in pathologicalAngiogenesis associated with tumors, intraocular neovascular disorders and other conditions.
Abstract: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.
8,942 citations
TL;DR: It is shown here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts.
Abstract: Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.
2,737 citations
TL;DR: The emerging principles of vascular growth provide exciting new perspectives, the translation of which might overcome the current limitations of pro- and antiangiogenic medicine.
2,278 citations
TL;DR: It is found that the zebrafish fli1 promoter is able to drive expression of enhanced green fluorescent protein (EGFP) in all blood vessels throughout embryogenesis, and these transgenic lines allow detailed analysis of both wild type and mutant embryonic vasculature.
1,939 citations