Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets.

Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative targets including vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known about such compounds and their multimodal anticancer properties. A compendium of heterocyclic synthetic and natural product multitarget anticancer compounds, their IC50, and biological targets of inhibition are therefore presented in this review.

Dimethyl itaconate attenuates palmitate-induced insulin resistance in skeletal muscle cells through the AMPK/FGF21/PPARδ-mediated suppression of inflammation.

AIM: Itaconate (ITA), a derivative of the tricarboxylic acid cycle, has been documented to have a direct antimicrobial effect by inhibiting isocitrate lyase and suppressing proinflammatory cytokines in LPS-treated macrophages. However, the effects of dimethyl ITA (DITA), a membrane-permeable derivative of ITA, on insulin signaling and inflammation in skeletal muscle in an obese state remain to be elucidated. Thus, this study was designed to investigate the effects of DITA on the impairment of insulin signaling and inflammation in palmitate-treated C2C12 myocytes. MATERIALS AND METHODS: Western blotting was used to determine the expression of insulin signaling associated genes, inflammatory markers, fibroblast growth factor 21 (FGF21), and PPARδ expression, as well as AMPK phosphorylation in mouse skeletal muscle cells. Secreted proinflammatory cytokine levels were detected by enzyme-linked immunosorbent assay. Insulin signaling was assessed by glucose uptake assay. KEY FINDINGS: Treating C2C12 myocytes with DITA attenuated palmitate-induced aggravation of insulin signaling markers, such as insulin receptor substrate-1 (IRS-1) and Akt phosphorylation and inflammatory markers, such as NFκB and IκB phosphorylation. AMPK phosphorylation, as well as PPARδ and myokine FGF21 expression, were enhanced in C2C12 myocytes by DITA treatment. siRNA-mediated suppression of AMPK or FGF21 expression abolished the effects of DITA on insulin resistance and inflammation in palmitate-treated C2C12 myocytes. SIGNIFICANCE: In sum, DITA suppresses inflammation through the AMPK/FGF21/PPARδ signaling, thereby alleviating insulin resistance in palmitate-treated C2C12 myocytes. The current study appears to be an essential basis for performing animal experiments to develop insulin resistance therapeutics.

Selective FGFR/FGF pathway inhibitors: inhibition strategies, clinical activities, resistance mutations, and future directions.

Introduction: Fibroblast growth factor receptor (FGFR)/fibroblast growth factor (FGF) is a pathway characterized by recurring alterations in cancer. Its dysregulations enhance cancer cell proliferation, survival, migration and invasion, as well as angiogenesis and immune evasion.Areas covered: FGFR/FGF selective inhibitors belong to a broad class of drugs with some being approved for specific indications and others under investigation in ongoing phase I and II clinical trials. In this review, all available clinical data from trials on selective FGFR/FGF inhibitors as well as described resistance mutations and mechanisms are presented. FGFR/FGF pathway inhibitors are classified according to the mechanism they employ to dampen/suppress signaling and to the preferred FGFR binding mode when X-ray crystal structure is available.Expert opinion: Data presented suggests the general actionability of FGFR1,2,3 mutations and fusions across histologies, whereas FGFR1,2,3 amplifications alone are poor predictors of response to tyrosine kinase inhibitors. Overexpression on immunohistochemistry (IHC) of FGF19, the stimulatory ligand of FGFR4, can predict response to FGFR selective inhibitors in hepatocellular carcinoma. Whereas IHC overexpression of FGFR1,2,3 is not sufficient to predict benefit from FGFR inhibitors across solid tumors. FGFR1,2,3 mRNA overexpression can predict response even in absence of structural alteration. Data on resistance mutations suggests the need for new inhibitors to overcome gatekeeper mutations.

Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment.

Locally advanced or metastatic urothelial bladder cancer (a/m UBC) is currently treated using platinum-based combination chemotherapy. Immune checkpoint inhibitors (ICIs) are the preferred second-line treatment options for cisplatin-eligible a/m UBC patients and as first-line options in cisplatin-ineligible settings. However, the response rates for ICI monotherapy are modest (~20%), which necessitates the exploration of alternative strategies. Dysregulated activation of fibroblast growth factor receptor (FGFR) signaling enhances tumor proliferation, survival, invasion, angiogenesis, and immune evasion. The recent U.S. Food and Drug Administration approval of erdafitinib and the emergence of other potent and selective FGFR inhibitors (FGFRis) have shifted the treatment paradigm for patients with a/m UBC harboring actionable FGFR2 or FGFR3 genomic alterations, who often have a minimal-to-modest response to ICIs. FGFRi-ICI combinations are therefore worth exploring, and their preliminary response rates and safety profiles are promising. In the present review, we summarize the impact of altered FGFR signaling on a/m UBC tumor evolution, the clinical development of FGFRis, the rationale for FGFRi-ICI combinations, current trials, and prospective research directions.

Chemical modification of NSC12 leads to a specific FGF-trap with antitumor activity in multiple myeloma.

Inhibition of FGF/FGFR signaling is a promising strategy for the treatment of malignances dependent from FGF stimulation, including multiple myeloma (MM). The steroidal derivative NSC12 (compound 1) is a pan-FGF trap endowed with antitumor activity in vivo. Chemical modifications of compound 1 were explored to investigate structure-activity relationships, focusing on the role of the bis(trifluoromethyl)1,3-propanediol chain, the stereochemistry at C20 and functionalization of C3 position. Our studies unveiled compound 25b, the pregnane 3-keto 20R derivative of compound 1 as an effective agent, blocking the proliferation of MM cells in vitro by inhibiting FGF-dependent receptor activation and slowing MM growth in vivo. Importantly, the absence of the hydroxyl group at C3 prevents binding to estrogen receptors, which might concur to the antitumor activity observed for compound 1, leading to a specific FGF/FGFR system inhibitor, and further supporting the role of FGFR in anticancer therapy in MM.

Switching from conventional therapy to burosumab injection has the potential to prevent nephrocalcinosis in patients with X-linked hypophosphatemic rickets.

OBJECTIVES: X-linked hypophosphatemic rickets (XLH) is a congenital fibroblast growth factor (FGF)23-related metabolic bone disease that is treated with active vitamin D and phosphate as conventional therapies. Complications of these therapies include nephrocalcinosis (NC) caused by excessive urine calcium and phosphate concentrations. Recently, an anti-FGF23 antibody, burosumab, was developed and reported to be effective in poorly-controlled or severe XLH patients. This study aimed to reveal the impact of switching treatments in relatively well-controlled XLH children with the Rickets Severity Scale less than 2.0. METHODS: The effects of the two treatments in eight relatively well-controlled XLH children with a mean age of 10.4 ± 1.9 years were compared retrospectively for the same treatment duration (31 ± 11 months) before and after the baseline. RESULTS: Actual doses of alfacalcidol and phosphate as conventional therapy were 150.9 ± 43.9 ng/kg and 27.5 ± 6.3 mg/kg per day, respectively. Renal echography revealed spotty NC in 8/8 patients, but no aggravation of NC was detected by switching treatments. Switching treatments increased TmP/GFR (p=0.002) and %TRP (p<0.001), and improved the high urine calcium/creatinine ratio to the normal range (p<0.001) although both treatments controlled disease markers equally. Additionally, low intact parathyroid hormone during conventional therapy was increased within the normal range by switching treatments. CONCLUSIONS: Our results suggest that a high dose of alfacalcidol was needed to control the disease, but it caused hypercalciuria and NC. We concluded that switching treatments in relatively well-controlled XLH children improved renal phosphate reabsorption and decreased urine calcium extraction, and may have the potential to prevent NC.

Dynamic extrinsic pacing of the HOX clock in human axial progenitors controls motor neuron subtype specification.

Rostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX genes within axial stem cells that fuel axial embryo elongation. Whether the pace of sequential activation of HOX genes, the 'HOX clock', is controlled by intrinsic chromatin-based timing mechanisms or by temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in human pluripotent stem cell-derived axial progenitors differentiating into diverse spinal cord motor neuron subtypes. We show that the progressive activation of caudal HOX genes is controlled by a dynamic increase in FGF signaling. Blocking the FGF pathway stalled induction of HOX genes, while a precocious increase of FGF, alone or with GDF11 ligand, accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The pacing of the HOX clock is thus dynamically regulated by exposure to secreted cues. Its manipulation by extrinsic factors provides synchronized access to multiple human neuronal subtypes of distinct rostro-caudal identities for basic and translational applications.This article has an associated 'The people behind the papers' interview.

1ɑ,25-Dihydroxyvitamin D3 promotes osteogenesis by down-regulating FGF23 in diabetic mice.

1ɑ,25-dihydroxyvitamin D3 (1,25D) and fibroblast growth factor 23 (FGF23) play important roles in bone metabolism through mutual regulation. However, the underlying mechanism between 1,25D and FGF23 in diabetes-induced bone metabolism disorders has not yet been elucidated. In this study, we investigated the effect of 1,25D on FGF23 under diabetic condition both in vitro and in vivo. The results showed that 1,25D down-regulated the expression of FGF23 in osteoblast significantly though a dose-dependent manner in vitro within high glucose environment. Western blot and immunofluorescence analysis indicated that 1,25D activated PI3K/Akt signalling through binding to vitamin D receptor (VDR), which inhibited the phosphorylation of the transcription factor Forkhead Box O1 (FOXO1). Decreased phosphorylation of FOXO1 down-regulated the expression Dickkopf-1 (DKK1), a well-known inhibitor of Wnt signalling. In addition, we observed that 1,25D remarkably ameliorated osteogenic phenotypic markers such as Ocn and Runx2 and rescued diabetes-induced bone loss in vivo. Our results suggested that 1,25D could promote osteogenesis though down-regulating FOXO1/FGF23 in diabetes.

Glucocorticoids dexamethasone and prednisolone suppress fibroblast growth factor 23 (FGF23).

Fibroblast growth factor 23 (FGF23) is a hormone mainly secreted by bone cells. Its most prominent effects are the regulation of renal phosphate reabsorption and calcitriol (active vitamin D, 1,25(OH)2D3) formation, effects dependent on its co-receptor αKlotho. Besides these actions, further paracrine and endocrine effects exist. The production of FGF23 is regulated by 1,25(OH)2D3, parathyroid hormone, dietary phosphate intake, iron status, as well as inflammation. Glucocorticoids are hormones with anti-inflammatory properties and are, therefore, widely used for acute and chronic inflammatory diseases, autoimmune disorders, and malignancies. The present study explored whether glucocorticoids influence the production of FGF23 in vitro as well as in mice. Fgf23 transcription was analyzed by semi-quantitative real-time PCR. Serum concentrations of FGF23 and 1,25(OH)2D3 were measured by ELISA. Urinary phosphate and Ca2+ excretion were determined in metabolic cages. As a result, in UMR106 rat osteoblast-like cells and in MC3T3-E1 cells, both, dexamethasone and prednisolone, downregulated Fgf23 transcription and FGF23 protein synthesis. Dexamethasone increased Dmp1 and Phex (encoding FGF23-regulating genes) as well as Nfkbia (encoding NFκB inhibitor IκBα) transcription in UMR106 cells. In mice, a single injection of dexamethasone or prednisolone was followed by a significant decrease of serum C-terminal and intact FGF23 concentration and bone Fgf23 mRNA expression within 12 h. These effects were paralleled by increased renal phosphate excretion and enhanced 1,25(OH)2D3 formation. We conclude that a single glucocorticoid treatment strongly downregulates the FGF23 plasma concentration. KEY MESSAGES: Glucocorticoids dexamethasone and prednisolone suppress the formation of bone-derived hormone fibroblast growth factor 23 (FGF23) in vitro. The effect is accompanied by an upregulation of Dmp1, Phex, and IκBα, negative regulators of FGF23, in UMR106 osteoblast-like cells. Glucocorticoid receptor antagonist RU-486 attenuates the effect of dexamethasone on FGF23, Dmp1, and Phex. In mice, a single glucocorticoid dose suppresses FGF23 and enhances 1,25(OH)2D3 (active vitamin D).

ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is characterized by high intertumor heterogeneity of genetic drivers. Two multitarget tyrosine kinase inhibitors (TKI), lenvatinib and sorafenib, are used as standard-of-care chemotherapeutics in patients with advanced HCC, but a stratification strategy has not been established because of a lack of efficacious biomarkers. Therefore, we sought biomarkers that indicate lenvatinib-susceptible HCC. EXPERIMENTAL DESIGN: We performed genetic screening of HCC driver genes involved in TKI susceptibility using a novel HCC mouse model in which tumor diversity of genetic drivers was recapitulated. A biomarker candidate was evaluated in human HCC cell lines. Secreted proteins from HCC cells were then screened using mass spectrometry. Serum and tumor levels of the biomarker candidates were analyzed for their association and prediction of overall survival in patients with HCC. RESULTS: We found that lenvatinib selectively eliminated FGF19-expressing tumors, whereas sorafenib eliminated MET- and NRAS-expressing tumors. FGF19 levels and lenvatinib susceptibility were correlated in HCC cell lines, and FGF19 inhibition eliminated lenvatinib susceptibility. Lenvatinib-resistant HCC cell lines, generated by long-term exposure to lenvatinib, showed FGF19 downregulation but were resensitized to lenvatinib by FGF19 reexpression. Thus, FGF19 is a tumor biomarker of lenvatinib-susceptible HCC. Proteome and secretome analyses identified ST6GAL1 as a tumor-derived secreted protein positively regulated by FGF19 in HCC cells. Serum ST6GAL1 levels were positively correlated with tumor FGF19 expression in patients with surgically resected HCC. Among patients with serum ST6GAL1-high HCC who underwent TKI therapy, lenvatinib therapy showed significantly better survival than sorafenib. CONCLUSIONS: Serum ST6GAL may be a novel biomarker that identifies lenvatinib-susceptible FGF19-driven HCC.

Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues.

Hereditary hypophosphatemic disorders, TIO, and CKD conditions are believed to be influenced by an excess of Fibroblast Growth Factor-23 (FGF-23) which activates a binary renal FGFRs / α-Klotho complex to regulate homeostatic metabolism of phosphate and vitamin D. Adaptive FGF-23 responses from CKD patients with excess FGF-23 frequently lead to increased mortality from cardiovascular disease. A reversibly binding small molecule therapeutic has yet to emerge from research and development in this area. Current outcomes described in this work highlight efforts related to lead identification and modification using organic synthesis of strategic analogues to probe structure-activity relationships and preliminarily define the pharmacophore of a computationally derived hit obtained from virtual high-throughput screening. Synthetic strategies for the initial hit and analogue preparation, as well as preliminary cellular in vitro assay results highlighting sub micromolar inhibition of the FGF-23 signaling sequence at a concentration well below cytotoxicity are reported herein.

Targeting Drugs Against Fibroblast Growth Factor(s)-Induced Cell Signaling.

BACKGROUND: The fibroblast growth factor (FGF) family is comprised of 23 highly regulated monomeric proteins that regulate a plethora of developmental and pathophysiological processes, including tissue repair, wound healing, angiogenesis, and embryonic development. Binding of FGF to fibroblast growth factor receptor (FGFR), a tyrosine kinase receptor, is facilitated by a glycosaminoglycan, heparin. Activated FGFRs phosphorylate the tyrosine kinase residues that mediate induction of downstream signaling pathways, such as RAS-MAPK, PI3K-AKT, PLCγ, and STAT. Dysregulation of the FGF/FGFR signaling occurs frequently in cancer due to gene amplification, FGF activating mutations, chromosomal rearrangements, integration, and oncogenic fusions. Aberrant FGFR signaling also affects organogenesis, embryonic development, tissue homeostasis, and has been associated with cell proliferation, angiogenesis, cancer, and other pathophysiological changes. OBJECTIVE: This comprehensive review will discuss the biology, chemistry, and functions of FGFs, and its current applications toward wound healing, diabetes, repair and regeneration of tissues, and fatty liver diseases. In addition, specific aberrations in FGFR signaling and drugs that target FGFR and aid in mitigating various disorders, such as cancer, are also discussed in detail. CONCLUSION: Inhibitors of FGFR signaling are promising drugs in the treatment of several types of cancers. The clinical benefits of FGF/FGFR targeting therapies are impeded due to the activation of other RTK signaling mechanisms or due to the mutations that abolish the drug inhibitory activity on FGFR. Thus, the development of drugs with a different mechanism of action for FGF/FGFR targeting therapies is the recent focus of several preclinical and clinical studies.

Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88.

The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.

FGF signaling mediates definitive endoderm formation by regulating epithelial-to-mesenchymal transition and cell proliferation.

FGF signaling pathway is imperative for definitive endoderm (DE) differentiation from human embryonic stem cells (hESCs), which always accompanies an epithelial-to-mesenchymal transition (EMT) process. However, whether there is an association between FGF signaling and the EMT during DE formation in vitro has remained elusive. In the present study, we identify that several FGF family members were significantly activated during the differentiation of hESCs toward DE. Inhibition of FGF signaling by an efficient and selective inhibitor BGJ398 abolishes both the EMT and DE induction by blocking the activation of the zinc-finger transcription factor SNAI1 which is a direct transcriptional repressor of cell adhesion protein CDH1. In addition, cell proliferation is also severely influenced by attenuating the FGF signaling. Collectively, we propose that the FGF signaling promotes the DE formation through mediating the EMT and cell proliferation.

FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression. Mice bearing high and low FGF19-expressing tumors were treated with FGF401 and/or vinorelbine, and the antitumor activity of both agents was assessed individually and in combination. Tumor vasculature and intratumoral hypoxia were also examined. High FGF19 expression was detected in 14.3% (9 of 63) of the HCC models tested and may represent a good target for HCC treatment. FGF401 potently inhibited the growth of high FGF19-expressing HCC models regardless of FGF19 gene amplification. Furthermore, FGF401 inhibited the FGF19/FGFR-4 signaling pathway, cell proliferation, and hypoxia, induced apoptosis and blood vessel normalization and prolonged the overall survival (OS) of mice bearing high FGF19 tumors. FGF401 synergistically acted with the microtubule-depolymerizing drug vinorelbine to further suppress tumor growth, promote apoptosis, and prolong the OS of mice bearing high FGF19 tumors, with no evidence of increased toxicity. Our study suggests that a subset of patients with high FGF19-expressing HCC tumors could benefit from FGF401 or FGF401/vinorelbine treatment. A high level of FGF19 in a tumor may serve as a potential biomarker for patient selection.

Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease.

Triclosan (TCS), employed as an antiseptic and disinfectant, comes into direct contact with humans through a plethora of consumer products and its rising environmental release. We have demonstrated that TCS promotes liver tumorigenesis in mice, yet the biological and molecular mechanisms by which TCS exerts its toxicity, especially in early stages of liver disease, are largely unexplored. When mice were fed a high-fat diet (HFD), we found that fatty liver and dyslipidemia are prominent early signs of liver abnormality induced by TCS. The presumably protective HFD-induced hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21) was blunted by TCS. TCS-altered Fgf21 expression aligned with aberrant expression of genes encoding metabolic enzymes manifested as profound systemic metabolic changes that disturb homeostasis of amino acids, fatty acids, and glucose. Using a type 1 diabetic animal model, TCS potentiates and accelerates the development of steatohepatitis and fibrosis, accompanied by increased levels of hepatic lipid droplets and oxidative stress. Analysis of fecal samples revealed that HFD-fed mice exhibited a reduction in fecal species richness, and that TCS further diminished microbial diversity and shifted the bacterial community toward lower Bacteriodetes and higher Firmicutes, resembling changes in microbiota composition in nonalcoholic steatohepatitis (NASH) patients. Using reverse-genetic approaches, we demonstrate that, along with HFD, TCS induces hepatic steatosis and steatohepatitis jointly regulated by the transcription factor ATF4 and the nuclear receptor PPARα, which participate in the transcriptional regulation of the Fgf21 gene. This study provides evidence linking nutritional imbalance and exposure to TCS with the progression of NASH.

FGF Expression in HPV16-positive and -negative SCC After Treatment With Small-molecule Tyrosine Kinase Inhibitors and Everolimus.

BACKGROUND: Targeted therapies in the treatment of head and neck squamous cell carcinoma (HNSCC) are subject to extensive research. Different mutations of genes belonging to the fibroblast growth factor (FGF) family have been detected in HNSCC. In this study, we examined the expression of FGF1 and FGF2 after treatment with small-molecule tyrosine kinase inhibitors (TKIs) and an inhibitor of mechanistic target of rapamycin (mTOR) in vitro using human papillomavirus (HPV)-positive and -negative SCC lines. MATERIALS AND METHODS: Cells of two human HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with 20 µmol/l of erlotinib, gefitinib, nilotinib, dasatinib, or everolimus for 24-96 h. Cell proliferation was assessed by proliferation assay and the protein concentrations of FGF1 and FGF2 by sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those for untreated HPV-negative SCC cells. RESULTS: FGF1 and FGF2 were detected in all three tested cell lines. The tested TKIs significantly (p<0.05 reduced) FGF1 expression in the UMSCC-11A cell line within the first 24 h. At later time points, the tested TKIs and everolimus significantly (p<0.05) increased FGF1 and FGF2 expression in HPV-negative and -positive cancer cell lines. The effect was stronger in the HPV-positive cell line. CONCLUSION: Alterations in FGF signalling are considered to be relevant drivers of tumourigenesis in some HNSCCs. Our results show that the expression of FGF1 and -2 can be influenced effectively by small-molecule TKIs and everolimus. Based on our data, future research should include combinations of specific FGF inhibitors, mTOR inhibitors and other TKIs in the treatment of HNSCC and research on FGF-mediated drug escape mechanisms.

Teneligliptin Promotes Bile Acid Synthesis and Attenuates Lipid Accumulation in Obese Mice by Targeting the KLF15-Fgf15 Pathway.

Bile acids (BAs) play essential physiological roles not only by facilitating the absorption and transport of nutrients but also by acting as a complex molecular signaling system. Reduced levels of BAs have been observed in obesity and other metabolic disorders. In the present study, we explored the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin on BA synthesis, both in vitro and in vivo. In our in vivo experiments, we found that teneligliptin increased the liver, ileal, and serum BA concentrations in mice undergoing teneligliptin treatment for 10 weeks. We further found that in mice fed a high-fat diet, teneligliptin prevented an increase in markers of obesity (body weight, total cholesterol, total triglyceride, adipocyte size) while increasing the total serum and ileal levels of BA. Mechanistically, teneligliptin increased BA synthesis through the alternative synthesis pathway, as the levels of both 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) along with downstream oxysterol 7α-hydroxylase (CYP7B1) but not sterol 12α-hydroxylase (CYP8B1) were increased. Importantly, teneligliptin suppressed the expression of the BA synthesis inhibitory factor Fgf15, which was mediated through phosphatidylinositol 3-kinase (PI3K)/AKT/Krüppel-like factor 15 (KLF15) signaling. Inhibition of KLF15 abolished this effect. Together, our results provide evidence of the potential benefit of teneligliptin in the treatment of metabolic disorders via increased BA production.

Burosumab in X-linked hypophosphatemia and perspective for chronic kidney disease.

PURPOSE OF REVIEW: Perturbations in phosphate and vitamin D homeostasis impacts skeletal health in children and adults. Study of inherited and acquired hypophosphatemic syndromes led to the discovery of fibroblast growth factor 23 (FGF23) as a potent regulator of phosphate and vitamin D metabolism, and advanced our understanding of the pathophysiology of mineral and bone disorder in chronic kidney disease (CKD-MBD). Here, we review a recently approved therapy for patients with X-linked hypophosphatemia (XLH) using a novel anti-FGF23 antibody, burosumab, and discuss the implications of such targeted therapy in CKD. RECENT FINDINGS: In children and adults with XLH, burosumab treatment significantly increased renal tubular phosphate reabsorption and normalized serum phosphorus concentrations. Prolonged treatment with burosumab showed a favorable safety profile, improved healing of rickets in children, and fractures and pseudofractures in adults. FGF23 excess in CKD is independently associated with left ventricular hypertrophy and cardiovascular mortality. Research strategies to lower FGF23 in animal models of CKD are rapidly advancing and a question that remains to be answered is whether FGF23 blockade will offer a new targeted intervention for disordered mineral metabolism in CKD. SUMMARY: Findings from recently concluded clinical trials in adults and children with XLH provide evidence for improved skeletal health with burosumab therapy with normalization of phosphate and vitamin D metabolism. Targeted anti-FGF23 antibody treatment of XLH has emerged as a novel therapeutic strategy to treat an inherited disorder of FGF23 excess.