Multiple Fibroblast Growth Factor Research Articles

Ligand bias underlies differential signaling of multiple FGFs via FGFR1.

The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.

The fibroblast growth factor system in cognitive disorders and dementia.

Cognitive impairment is the core precursor to dementia and other cognitive disorders. Current hypotheses suggest that they share a common pathological basis, such as inflammation, restricted neurogenesis, neuroendocrine disorders, and the destruction of neurovascular units. Fibroblast growth factors (FGFs) are cell growth factors that play essential roles in various pathophysiological processes via paracrine or autocrine pathways. This system consists of FGFs and their receptors (FGFRs), which may hold tremendous potential to become a new biological marker in the diagnosis of dementia and other cognitive disorders, and serve as a potential target for drug development against dementia and cognitive function impairment. Here, we review the available evidence detailing the relevant pathways mediated by multiple FGFs and FGFRs, and recent studies examining their role in the pathogenesis and treatment of cognitive disorders and dementia.

Identification of rare loss-of-function variants in FAM3B associated with non-syndromic orofacial clefts

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders and cause serious problems with the appearance, orofacial function and mental health of the patients. The fibroblast growth factor (FGF) signaling pathway is critical for several aspects of craniofacial development and loss-of-function mutations of coding genes for multiple FGFs and FGFRs can lead to OFCs. We recently characterized FAM3B as a novel ligand of FGF signaling, which, through binding to FGFRs and activating downstream ERK, regulates craniofacial development in Xenopus. In this study, we identify two rare variants in FAM3B (p.Q61R and p.D128G) via target region sequencing of FAM3B on 144 unrelated sporadic patients with non-syndromic OFCs (NSOFCs). Bioinformatic analysis predict that these two variants are likely to be damaging and biochemical experiments show that these two variants weaken the FGF ligand activity of FAM3B by decreasing its expression and thus secretion. In summary, our results indicate that FAM3B is a novel candidate gene for NSOFCs in humans.

Identification, Characterization and Functional Analysis of Fibroblast Growth Factors in Black Rockfish (Sebastes schlegelii)

Fibroblast growth factors (FGFs) are short polypeptides that play essential roles in various cellular biological processes, including cell migration, proliferation, and differentiation, as well as tissue regeneration, immune response, and organogenesis. However, studies focusing on the characterization and function of FGF genes in teleost fishes are still limited. In this study, we identified and characterized expression patterns of 24 FGF genes in various tissues of embryonic and adult specimens of the black rockfish (Sebates schlegelii). Nine FGF genes were found to play essential roles in myoblast differentiation, as well as muscle development and recovery in juvelines of S. schlegelii. Moreover, sex-biased expression pattern of multiple FGF genes was recorded in the species' gonads during its development. Among them, expression of the FGF1 gene was recorded in interstitial and sertoli cells of testes, promoting germ-cell proliferation and differentiation. In sum, the obtained results enabled systematic and functional characterization of FGF genes in S. schlegelii, laying a foundation for further studies on FGF genes in other large teleost fishes.

Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells.

It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) play a fundamental role in liver immunology. However, how FGF signaling in HSCs regulates liver inflammation remains unclear. Here, we report that FGF promoted NF-κB signaling, an inflammatory pathway, in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by FGFR1 tyrosine kinase inhibitor. After stimulating HSCs with proinflammatory cytokines, expression of multiple FGF ligands was significantly increased. However, disruption of FGF signaling with FGFR inhibitors prominently reduced the apoptosis, inflammatory response, NF-κB nuclear translocation, and expression of matrix metalloproteinase-9 (MMP-9) induced by TNFα in HSCs. Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A)-induced acutely injured liver. Unlike canonic FGFs that elicit signals through activating the FGFR–heparan sulfate complex, FGF21 activates the FGFR–KLB complex and elicits a different set of signals. Therefore, the finding here indicates the urgency of developing pathway-specific inhibitors that only suppress canonical FGF, but not non-canonical FGF21, signaling for alleviating inflammation in the liver, which is presented in all stages of diseased liver.

Nanodiamonds as “artificial proteins”: Regulation of a cell signalling system using low nanomolar solutions of inorganic nanocrystals

The blocking of specific protein-protein interactions using nanoparticles is an emerging alternative to small molecule-based therapeutic interventions. However, the nanoparticles designed as “artificial proteins” generally require modification of their surface with (bio)organic molecules and/or polymers to ensure their selectivity and specificity of action. Here, we show that nanosized diamond crystals (nanodiamonds, NDs) without any synthetically installed (bio)organic interface enable the specific and efficient targeting of the family of extracellular signalling molecules known as fibroblast growth factors (FGFs). We found that low nanomolar solutions of detonation NDs with positive ζ-potential strongly associate with multiple FGF ligands present at sub-nanomolar concentrations and effectively neutralize the effects of FGF signalling in cells without interfering with other growth factor systems and serum proteins unrelated to FGFs. We identified an evolutionarily conserved FGF recognition motif, ∼17 amino acids long, that contributes to the selectivity of the ND-FGF interaction. In addition, we inserted this motif into a de novo constructed chimeric protein, which significantly improved its interaction with NDs. We demonstrated that the interaction of NDs, as purely inorganic nanoparticles, with proteins can mitigate pathological FGF signalling and promote the restoration of cartilage growth in a mouse limb explant model. Based on our observations, we foresee that NDs may potentially be applied as nanotherapeutics to neutralize disease-related activities of FGFs in vivo.

The Role of Fibroblast Growth Factors in Tooth Development and Incisor Renewal.

The mineralized tissue of the tooth is composed of enamel, dentin, cementum, and alveolar bone; enamel is a calcified tissue with no living cells that originates from oral ectoderm, while the three other tissues derive from the cranial neural crest. The fibroblast growth factors (FGFs) are critical during the tooth development. Accumulating evidence has shown that the formation of dental tissues, that is, enamel, dentin, and supporting alveolar bone, as well as the development and homeostasis of the stem cells in the continuously growing mouse incisor is mediated by multiple FGF family members. This review discusses the role of FGF signaling in these mineralized tissues, trying to separate its different functions and highlighting the crosstalk between FGFs and other signaling pathways.

Regulation of skeletal muscle stem cells by fibroblast growth factors.

Fibroblast growth factors (FGFs) are essential for self-renewal of skeletal muscle stem cells (satellite cells) and required for maintenance and repair of skeletal muscle. Satellite cells express high levels of FGF receptors 1 and 4, low levels of FGF receptor 3, and little or no detectable FGF receptor 2. Of the multiple FGFs that influence satellite cell function in culture, FGF2 and FGF6 are the only members that regulate satellite cell function in vivo by activating ERK MAPK, p38α/β MAPKs, PI3 kinase, PLCγ and STATs. Regulation of FGF signaling is complex in satellite cells, requiring Syndecan-4, a heparan sulfate proteoglycan, as well as ß1-integrin and fibronectin. During aging, reduced responsiveness to FGF diminishes satellite cell self-renewal, leading to impaired skeletal muscle regeneration and depletion of satellite cells. Mislocalization of ß1-integrin, reductions in fibronectin, and alterations in heparan sulfate content all contribute to reduced FGF responsiveness in satellite cells. How these cell surface proteins regulate satellite cell self-renewal is incompletely understood. Here we summarize the current knowledge, highlighting the role(s) for FGF signaling in skeletal muscle regeneration, satellite cell behavior, and age-induced muscle wasting. Developmental Dynamics 246:359-367, 2017. © 2017 Wiley Periodicals, Inc.

Abstract 1174: AZD4547 and AZD5363 synergistically inhibit prostate cancer progression by modulating MAPK and AKT activation

Abstract Prostate cancer (PCa) is the second most common cancer and the second most common cause of cancer mortality in men in the United States. Multiple approved therapies target the androgen signaling axis in this metastatic disease, however, after advancing to the androgen-independent stage, PCa is unresponsive to androgen ablation therapy and is refractory to further curative treatment. Recent advances have demonstrated that two intracellular signaling pathways promote prostate cancer progression, one is the Fibroblast Growth Factor (FGF) pathway included multiple FGFs and 4 kinds of FGF receptors (FGFR), which remains activated in the cancer cells, the other is the oncogenic PI3K/AKT pathway, which is constantly active due to the loss of an important tumor suppressor gene. Targeted inhibition of FGF and AKT signaling pathways has shown promising both in vitro and in vivo studies. However, FGFR or AKT inhibitor, as a single agent, would result in a reciprocal feedback loop. Therefore, it is imperative that both pathways be targeted simultaneously in the treatment of advanced prostate cancer. In this study, we evaluated the effect of combined treatment of FGFR inhibitor AZD4547 and AKT inhibitor AZD5363 on PCa progression. Proliferation assay shows that AZD4547 just weakly, or not inhibits PCa cell proliferation, AZD5363 significantly inhibits PCa cell proliferation; the combined treatment of AZD4547 and AZD5363 shows similar inhibition effect to AZD5363. Both AZD4547 and AZD5363 inhibit PCa cell anchorage-independent growth and invasion, which are synergistically decrease by the combined treatment. AZD4547 significantly inhibits phosporylation of FGFR1 and FGFR4 in PCa cells; AZD5363 increases FGFR1 and FGFR4 phosphorylation, which was significantly repressed in combined treatment. The activation of FGFR2α, MEK1/2, and Erk1/2 in PCa cells was remarkably inhibited by AZD4547 but increased by AZD5363, and synergistically inhibited by the combined treatment. AKT was hyperphosphorylated by AZD5363 and inhibited by AZD4547. The phosporylation of AKT downstream molecules PRAS40, GSK3β and S6, was slightly decreased by AZD4547 but strongly inhibited by AZD5363 and the combined treatment. Both AZD4547 and AZD5363 suppress STAT3 phosphorylation in PCa cells and the combind treatment shows synergistic inhibition effect. Both AZD4547 and AZD5363 promote AR and PTEN expression at both RNA and protein levels in VCaP and 22RV1cells, and the combination treatment remains the promotion effect. In LNCaP cells, AZD5363, but not AZD4547, stimulates AR mRNA and protein expression, which keep increased in combined treatment. This study provides a preclinical proof of concept that combination of a FGFR inhibitor with an AKT inhibitor has a profound potential to treat PCa. Acknowledgement: This project was supported by the DOD Prostate Cancer Program, PCRP-IDEA-PC120481 (Ittmann), the Prostate Cancer Foundation (Ittmann) Citation Format: Shu Feng, Michael Ittmann. AZD4547 and AZD5363 synergistically inhibit prostate cancer progression by modulating MAPK and AKT activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1174.

Efficient regulation of branching morphogenesis via fibroblast growth factor receptor 2c in early-stage embryonic mouse salivary glands

Salivary gland (SG) defects have a wide range of health implications, including xerostomia, bacterial infections, and oral health issues. Branching morphogenesis is critical for SG development. A clear understanding of the mechanisms underlying this process will accelerate SG regeneration studies. Fibroblast growth factor receptor 2 (FGFR2) interacts with multiple fibroblast growth factors (FGFs), which promote development. FGFR2 consists of two isoforms, FGFR2b and FGFR2c. FGFR2b is critical for SG development, but little is known about the expression and function of FGFR2c. We investigated the expression of all FGFR family members in fetal SGs between embryonic day 12.5 (E12.5) and E18.5. Based on RT-PCR, we observed an increase in the expression of not only Fgfr2b, but also Fgfr2c in early-stage embryonic mouse SGs, suggesting that FGFR2c is related to SG development. The branch number decreased in response to exogenous FGF2 stimulation, and this effect was suppressed by a mouse anti-FGFR2c neutralizing antibody (NA) and siRNA targeting FGFR2c, whereas FGFR2b signaling was not inhibited. Moreover, the expression of marker genes related to EMT was induced by FGF2, and this expression was suppressed by the NA. These results suggested that branching morphogenesis in SGs is regulated by FGFR2c, in addition to FGFR2b. Interestingly, FGFR2c signaling also led to increased fgf10 expression, and this increase was suppressed by the NA. FGFR2c signaling regulates branching morphogenesis through the activation of FGFR2b signaling via increased FGF10 autocrine. These results provide new insight into the mechanisms by which crosstalk between FGFR2b and FGFR2c results in efficient branching morphogenesis.

A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors

Fibroblast growth factors (FGFs) play important roles in multiple cancers by supporting tumor growth and angiogenesis. FP-1039 (GSK3052230) is a FGF ligand trap consisting of the extracellular domain of FGF receptor 1 (FGFR1) fused with the Fc region of IgG1. FP-1039 binds and neutralizes multiple FGFs that normally bind FGFR1. The primary objective of this phase I study was to evaluate the safety and tolerability of FP-1039. Eligible patients with metastatic or locally advanced solid tumors for which standard treatments were ineffective were treated with weekly doses of FP-1039 for 4 weeks, followed by 2 weeks observation. Thirty-nine subjects received a mean of 6 infusions of FP-1039 at doses ranging from 0.5 to 16 mg/kg weekly, with no maximally tolerated dose identified. Grade 3 or greater treatment emergent adverse events were uncommon. Four dose-limiting toxicities were reported at doses of 0.75 mg/kg (urticaria), 1 mg/kg (intestinal perforation and neutropenia), and 16 mg/kg (muscular weakness). Drug exposure was dose proportional, and the terminal elimination half-life was 2.6-3.9 days following a single dose. Target engagement as measured by low free plasma FGF2 levels was achieved. FGF pathway dysregulation was uncommon. No objective responses were observed. In nonselected cancer patients with advanced disease, treatment with FP-1039 was well tolerated and toxicities associated with small molecule drugs that inhibit FGFR tyrosine kinases, including hyperphosphatemia, were not observed. Further studies of FP-1039 in patients selected for FGF pathway dysregulation, who are most likely to benefit, are now underway.

Control of lens development by Lhx2-regulated neuroretinal FGFs.

Fibroblast growth factor (FGF) signaling is an essential regulator of lens epithelial cell proliferation and survival, as well as lens fiber cell differentiation. However, the identities of these FGF factors, their source tissue and the genes that regulate their synthesis are unknown. We have found that Chx10-Cre;Lhx2lox/lox mice, which selectively lack Lhx2 expression in neuroretina from E10.5, showed an early arrest in lens fiber development along with severe microphthalmia. These mutant animals showed reduced expression of multiple neuroretina-expressed FGFs and canonical FGF-regulated genes in neuroretina. When FGF expression was genetically restored in Lhx2-deficient neuroretina of Chx10-Cre;Lhx2lox/lox mice, we observed a partial but nonetheless substantial rescue of the defects in lens cell proliferation, survival and fiber differentiation. These data demonstrate that neuroretinal expression of Lhx2 and neuroretina-derived FGF factors are crucial for lens fiber development in vivo.

Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells

Human airway basal cells are the stem (or progenitor) population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of basal cells allows for potential paracrine signaling between them and the underlying non-epithelial stromal cells. In support of this, we have previously demonstrated that endothelial cells support growth of basal cells during co-culture through vascular endothelial growth factor A (VEGFA)-mediated signaling. Building on these findings, we found, by RNA sequencing analysis, that basal cells expressed multiple fibroblast growth factor (FGF) ligands (FGF2, FGF5, FGF11 and FGF13) and that only FGF2 and FGF5 were capable of functioning in a paracrine manner to activate classical FGF receptor (FGFR) signaling. Antibody-mediated blocking of FGFR1 during basal-cell–endothelial-cell co-culture significantly reduced the endothelial-cell-dependent basal cell growth. Stimulation of endothelial cells with basal-cell-derived growth factors induced endothelial cell expression of matrix metallopeptidase 14 (MMP14), and short hairpin RNA (shRNA)-mediated knockdown of endothelial cell MMP14 significantly reduced the endothelial-cell-dependent growth of basal cells. Overall, these data characterize a new growth-factor-mediated reciprocal ‘crosstalk’ between human airway basal cells and endothelial cells that regulates proliferation of basal cells.

Fgf signaling controls the telencephalic distribution of Fgf-expressing progenitors generated in the rostral patterning center.

BackgroundThe rostral patterning center (RPC) secretes multiple fibroblast growth factors (Fgfs) essential for telencephalon growth and patterning. Fgf expression patterns suggest that they mark functionally distinct RPC subdomains. We generated Fgf8CreER and Fgf17CreER mice and used them to analyze the lineages of Fgf8- versus Fgf17-expressing RPC cells.ResultsBoth lineages contributed to medial structures of the rostroventral telencephalon structures including the septum and medial prefrontral cortex. In addition, RPC-derived progenitors were observed in other regions of the early telencephalic neuroepithelium and generated neurons in the olfactory bulb, neocortex, and basal ganglia. Surprisingly, Fgf8+ RPC progenitors generated the majority of basal ganglia cholinergic neurons. Compared to the Fgf8 lineage, the Fgf17 lineage was more restricted in its early dispersion and its contributions to the telencephalon. Mutant studies suggested that Fgf8 and Fgf17 restrict spread of RPC progenitor subpopulations.ConclusionsWe identified the RPC as an important source of progenitors that contribute broadly to the telencephalon and found that two molecularly distinct progenitor subtypes in the RPC make different contributions to the developing forebrain.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-015-0037-7) contains supplementary material, which is available to authorized users.

Instability restricts signaling of multiple fibroblast growth factors.

Fibroblast growth factors (FGFs) deliver extracellular signals that govern many developmental and regenerative processes, but the mechanisms regulating FGF signaling remain incompletely understood. Here, we explored the relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family. We report that FGF1, FGF3, FGF4, FGF6, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 exist as unstable proteins, which are rapidly degraded in cell cultivation media. Biological activity of FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, and FGF20 is limited by their instability, manifesting as failure to activate FGF receptor signal transduction over long periods of time, and influence specific cell behavior in vitro and in vivo. Stabilization via exogenous heparin binding, introduction of stabilizing mutations or lowering the cell cultivation temperature rescues signaling of unstable FGFs. Thus, the intrinsic ligand instability is an important elementary level of regulation in the FGF signaling system.

Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells.

Human airway basal cells are the stem (or progenitor) population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of basal cells allows for potential paracrine signaling between them and the underlying non-epithelial stromal cells. In support of this, we have previously demonstrated that endothelial cells support growth of basal cells during co-culture through vascular endothelial growth factor A (VEGFA)-mediated signaling. Building on these findings, we found, by RNA sequencing analysis, that basal cells expressed multiple fibroblast growth factor (FGF) ligands (FGF2, FGF5, FGF11 and FGF13) and that only FGF2 and FGF5 were capable of functioning in a paracrine manner to activate classical FGF receptor (FGFR) signaling. Antibody-mediated blocking of FGFR1 during basal-cell-endothelial-cell co-culture significantly reduced the endothelial-cell-dependent basal cell growth. Stimulation of endothelial cells with basal-cell-derived growth factors induced endothelial cell expression of matrix metallopeptidase 14 (MMP14), and short hairpin RNA (shRNA)-mediated knockdown of endothelial cell MMP14 significantly reduced the endothelial-cell-dependent growth of basal cells. Overall, these data characterize a new growth-factor-mediated reciprocal 'crosstalk' between human airway basal cells and endothelial cells that regulates proliferation of basal cells.

Fibroblast Growth Factor Signaling Affects Vascular Outgrowth and Is Required for the Maintenance of Blood Vessel Integrity

Angiogenesis contributes to the development of numerous disorders. Even though fibroblast growth factors (FGFs) were discovered as mediators of angiogenesis more than 30 years ago, their role in developmental angiogenesis still remains elusive. We use a recently described chemical probe, SSR128129E (SSR), that selectively inhibits the action of multiple FGF receptors (FGFRs), in combination with the zebrafish model to examine the role of FGF signaling in vascular development. We observe that while FGFR signaling is less important for vessel guidance, it affects vascular outgrowth and is especially required for the maintenance of blood vessel integrity by ensuring proper cell-cell junctions between endothelial cells. In conclusion, our work illustrates the power of a small molecule probe to reveal insights into blood vessel formation and stabilization and thus of broad interest to the vascular biology community.

Targeting fibroblast growth factors in cancer

Fibroblast growth factors (FGFs) have been implicated in multiple aspects of cancer development and growth for over 20 years [1]. Research has shown that FGFs have a role in a) directly promoting cancer cell growth, b) tumor angiogenesis, and c) more speculatively, the survival of a group of cancer cells called “tumor stem cells” that are particularly difficult to target with current therapies. Therefore, inhibition of the FGF pathway has “multiple ways to win” as a cancer therapeutic. The FGF family is large: it has 22 different ligand members (the FGFs) that bind to 4 different receptors (the FGFRs). FGFRs are type 1 transmembrane receptors containing a large extracellular domain that bind FGFs, a transmembrane domain and an intracellular signaling domain that contains a tyrosine kinase domain. Many ligands of the FGF family have been implicated in the initiation, promotion and maintenance of cancer. We term these cancer-related FGFs “the classical FGFs”. They play essential roles during normal embryonic development, but their roles are less important during normal adult life. During cancer development some tumors hijack the FGF pathway, thereby increasing the levels of expression of many FGF family members to promote growth and tumor metastasis. A sub-group of the FGF family termed the hormonal FGFs has a more homeostatic role in the adult that includes regulating phosphate levels, vitamin D metabolism (FGF-23), bile acid production (FGF-19) and glucose utilization (FGF-21). Hormonal FGFs require co-receptors such and α-Klotho or β-Klotho to bind and signal via FGFRs [2]. FP-1039 (also known as HGS1036 or GSK3052230) is designed around FGF receptor 1 (FGFR1). FP-1039 consists of the FGFR1 extracellular domain fused to the Fc domain of human IgG1. The Fc domain confers a number of favorable characteristics to FP-1039 including excellent pharmacokinetics. FP-1039 binds only to select FGFs – with the highest affinity for the “classical FGFs” that have been implicated in tumor growth. As described in our recent paper [3], FP-1039 does not bind to the hormonal FGFs. Accordingly, FP-1039 targets the “bad” FGFs that drive cancer growth and at the same time avoids inhibition of the hormonal FGFs and potential related toxicities (Fig. ​(Fig.11). Figure 1 The family of FGF receptors and FGF ligands Several companies are targeting the FGF-FGFR signaling pathway for cancer therapeutics [4]. This includes small molecule tyrosine kinase inhibitors, which inhibit the signaling of the intracellular kinase domain; they tend to have broad specificity across FGF receptors and consequently block most FGF receptor signaling. In some instances they also inhibit other classes of receptors (e.g., VEGF receptors). Importantly these pan-FGFR inhibitors also block the activity of the hormonal FGFs which may have unwanted side effects. For example, AZD4547 has reported hyperphosphatemia in 25 of 69 treated patients in a recently reported Phase 1clinical trial [5]. Similar phosphate elevations have also been reported in preclinical toxicology studies of small molecule FGFR inhibitors [6]. These side effects may potentially be minimized by a low-phosphate diet, with drugs that remove phosphate from the blood (chelation therapy), or stopping the FGF inhibitor drug for a period of time. Other companies have tried to specifically target individual FGF receptors using monoclonal antibodies, although in some cases this has met with unexpected toxicity, as was previously shown with a monoclonal antibody directed against FGFR1 that resulted in rapid weight loss in animal models [7]. Hyperphosphatemia and weight loss have not been observed with FP-1039 [8]. While targeting individual FGF ligands may have anti-tumor efficacy in the absence of toxicity (e.g., FGF-2), FP-1039 has the advantage in that it is capable of blocking multiple FGFs that have been implicated in cancer. As such, FP-1039 has the potential for therapeutic benefit in a broader context than antibodies that targeting a single FGF. As a result, FP-1039 is getting closer to the goal of treating the right patient with the right drug for the right target. First, FP-1039 has the ability to target and inhibit only “the classical FGFs” and not the hormonal FGFs, thus avoiding potential toxicities associated with pan-FGFR inhibition. Secondly, the direct action against a family of ligands that have been shown to promote tumor cell growth and in parallel inhibit tumor blood vessels, allows clear identification of the target and patient. Our work has shown that FP-1039 is particularly effective against tumor models that harbor amplification of the FGFR1 gene. Such amplifications have been observed in lung cancer, including squamous non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), as well as breast cancer. The presence of the FGFR1 amplification may provide a biomarker to identify patients that will be particularly sensitive to therapy by FP-1039 and therefore, add to the list of drugs that offer a precision medicine approach to cancer therapy.

Divergent requirements for fibroblast growth factor signaling in zebrafish maxillary barbel and caudal fin regeneration

The zebrafish maxillary barbel is an integumentary organ containing skin, glands, pigment cells, taste buds, nerves, and endothelial vessels. The maxillary barbel can regenerate (LeClair & Topczewski 2010); however, little is known about its molecular regulation. We have studied fibroblast growth factor (FGF) pathway molecules during barbel regeneration, comparing this system to a well-known regenerating appendage, the zebrafish caudal fin. Multiple FGF ligands (fgf20a, fgf24), receptors (fgfr1-4) and downstream targets (pea3, il17d) are expressed in normal and regenerating barbel tissue, confirming FGF activation. To test if specific FGF pathways were required for barbel regeneration, we performed simultaneous barbel and caudal fin amputations in two temperature-dependent zebrafish lines. Zebrafish homozygous for a point mutation in fgf20a, a factor essential for caudal fin blastema formation, regrew maxillary barbels normally, indicating that the requirement for this ligand is appendage-specific. Global overexpression of a dominant negative FGF receptor, Tg(hsp70l:dn-fgfr1:EGFP)(pd1) completely blocked fin outgrowth but only partially inhibited barbel outgrowth, suggesting reduced requirements for FGFs in barbel tissue. Maxillary barbels expressing dn-fgfr1 regenerated peripheral nerves, dermal connective tissue, endothelial tubes, and a glandular epithelium; in contrast to a recent report in which dn-fgfr1 overexpression blocks pharyngeal taste bud formation in zebrafish larvae (Kapsimali et al. 2011), we observed robust formation of calretinin-positive tastebuds. These are the first experiments to explore the molecular mechanisms of maxillary barbel regeneration. Our results suggest heterogeneous requirements for FGF signaling in the regeneration of different zebrafish appendages (caudal fin versus maxillary barbel) and taste buds of different embryonic origin (pharyngeal endoderm versus barbel ectoderm).

Implication of fibroblast growth factors in epileptogenesis-associated circuit rearrangements

The transformation of a normal brain in epileptic (epileptogenesis) is associated with extensive morpho-functional alterations, including cell death, axonal and dendritic plasticity, neurogenesis, and others. Neurotrophic factors (NTFs) appear to be very strongly implicated in these phenomena. In this review, we focus on the involvement of fibroblast growth factor (FGF) family members. Available data demonstrate that the FGFs are highly involved in the generation of the morpho-functional alterations in brain circuitries associated with epileptogenesis. For example, data on FGF2, the most studied member, suggest that it may be implicated both in seizure susceptibility and in seizure-induced plasticity, exerting different, and apparently contrasting effects: favoring acute seizures but reducing seizure-induced cell death. Even if many FGF members are still unexplored and very limited information is available on the FGF receptors, a complex and fascinating picture is emerging: multiple FGFs producing synergic or antagonistic effects one with another (and/or with other NTFs) on biological parameters that, in turn, facilitate or oppose transformation of the normal tissue in epileptic. In principle, identifying key elements in these phenomena may lead to effective therapies, but reaching this goal will require confronting a huge complexity. One first step could be to generate a “neurotrophicome” listing the FGFs (and all other NTFs) that are active during epileptogenesis. This should include identification of the extent to which each NTF is active (concentrations at the site of action); how it is active (local representation of receptor subtypes); when in the natural history of disease this occurs; how the NTF at hand will possibly interact with other NTFs. This is extraordinarily challenging, but holds the promise of a better understanding of epileptogenesis and, at large, of brain function.