Search

Comprehensive genomic profiling has an emerging role in cancer therapeutics. As treatment options remain needed for advanced cancers, patients are relying increasingly more on tumor genomic alterations as possible targets for cancer treatment. Frequent tumor fibroblast growth factor receptor (FGFR) alterations are seen in many cancers, and include genetic amplifications, mutations, rearrangements and fusions. FGFR inhibitors target these receptor alterations and show promise as a drug class. Currently 2 medications are currently FDA approved: erdafitinib and pemigatinib. Through the FDA accelerated approval process, erdafitinib is indicated to treat metastatic urothelial carcinoma with FGFR2 and FGFR3 alterations, whereas pemigatinib is indicated to treat unresectable cholangiocarcinoma with FGFR2 alterations. Despite growing knowledge about such advanced cancers, treatment is usually palliative. With multiple FGFR inhibitors in the pipeline, further FDA approvals are possible, and it is likely their role in therapy will extend to other cancer types. This review outlines erdafitinib, pemigatinib, their role in cancer, as well as outlining the possible future use of other FGFR inhibitors in urothelial carcinoma, cholangiocarcinoma, and other malignancies. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic disease, characterized by the growth of endometrial-like cells outside the uterine cavity. Due to its complex pathophysiology, a totally resolving cure is yet to be found. The aim of this study was to compare the therapeutic efficacy of AZD4547, a novel fibroblast growth factor receptor inhibitor (FGFRI), with a well characterized progestin, etonogestrel (ENG) using a validated in vivo mouse model of endometriosis. Endometriosis was induced by transplanting uterine fragments from donor mice in proestrus into the peritoneal cavity of recipient mice, which then developed into cyst-like lesions. AZD4547 and ENG were administered systemically either from the day of endometriosis induction or 2-weeks post-surgery. After 20 days of treatment, the lesions were harvested; their size and weight were measured and analyzed histologically or by qRT-PCR. Stage of estrous cycle was monitored throughout. Compared to vehicle, AZD4547 (25 mg/kg) was most effective in counteracting lesion growth when treating from day of surgery and 2 weeks after; ENG (0.8 mg/kg) was similarly effective in reducing lesion growth but only when administered from day of surgery. Each downregulated FGFR gene expression (p < 0.05). AZD4547 at all doses and ENG (0.008 mg/kg) caused no disturbance to the estrous cycle. ENG at 0.08 and 0.8 mg/kg was associated with partial or complete estrous cycle disruption and hyperemia of the uteri. AZD4547 and ENG both attenuated endometriotic lesion size, but only AZD4547 did not disrupt the estrous cycle, suggesting that targeting of FGFR is worthy of further investigation as a novel treatment for endometriosis. [ABSTRACT FROM AUTHOR]

Copyright of HNO is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Rationale: Reconstruction of hair follicles (HFs) and eccrine sweat glands (ESGs) is essential for functional skin regeneration. In skin reconstruction research, we found that foreskin-derived epidermal cells reconstructed HF organoids unidirectionally, but not ESG organoids. Methods: To investigate key genes and pathways influencing the fate of ESG and HF, a transcriptome profiling of ESG placode-containing skin and HF placode-containing skin was employed, and key DEGs were identified and validated by RT-qPCR and immunofluorescence staining in mice and rats. Subsequently, adult human epidermal cell-derived organoids were reconstructed to probe functional roles and mechanisms of FGF7 and FGF10 by series of approaches integrating RT-qPCR, immunofluorescence-staining, WB, apoptosis assay, and pathway interference assay. Results: All members of FGF7 subfamily were among the key DEGs screened, the differential expression of FGF7 and FGF10 and their receptors FGFR1/FGFR2 was verified between ESG placode-containing skin and HF placode-containing skin. In vivo and in vitro Matrigel plug models showed that both FGF7 and FGF10 promoted fate transition of human epidermal cell-derived organoids to ESG phenotype organoids, FGF7 and FGF10 had a synergistic effect, and mainly function through the FGFR1/2-MEK1/2-ERK1/2 pathway. Conclusions: Adult epidermal cells can be manipulated to reconstruct personalized HF and ESG to meet different needs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here., Patients and Methods: Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK)., Results: Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively., Conclusions: Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations., Competing Interests: Disclosure VS reports scientific advisory board participation for Relay Therapeutics, Incyte, Novartis, Eli Lilly/Loxo Oncology, Roche, Pfizer, Jazz Pharmaceuticals, Bayer, AbbVie, Regeneron, Novartis, Clinical Care Communications, Invited Speaker. KPP reports consulting or advisory roles for Basilea and Turning Point Therapeutics and research funding paid to the institution from 3D Medicines, AbbVie, ADC Therapeutics, Amgen, Anheart Therapeutics, Bayer, Calithera Biosciences, Daiichi Sankyo, EMD Serono, F-star, Incyte, Jounce Therapeutics, Lilly, Linnaeus Therapeutics, MabSpace Biosciences, MedImmune, Merck, Mersana, Mirati Therapeutics, Peloton Therapeutics, Pfizer, Regeneron Pharmaceuticals, Inc., Syros Pharmaceuticals, Tempest Therapeutics, and Treadwell Therapeutics. DM received consulting fees from AbbVie, Arcus, Lilly, and Mirati. Research grants or funds were received from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Epicentrx, Incyte, Lilly, Merck, Novartis, Pfizer, Roche, Surface, and Y-mabs. NBM received research funding paid directly to the institution from Actuate Therapeutics, Amphivena Therapeutics, Aravive Inc., AstraZeneca, BioMed Valley Discoveries, Compass Therapeutics, Erytech Pharma, Genentech, Incyte, Leap Therapeutics, Merck Sharp and Dohme, Mereo BioPharma Group, NuCana, Repare Therapeutics, and Syros Pharmaceuticals. IS received research funding paid directly to the institution from Alligator Bioscience, AstraZeneca, Bristol Myers Squibb, Cantargia AB, Genentech, Genmab, Incyte, Loxo/Bayer, Loxo/Lilly, MSD, Novartis, Orion, Roche, Pfizer, Puma Biotechnology, and Symphogen; and support for attending meetings and/or travel expenses from AstraZeneca, Incyte, Merck, and Pfizer. MLV and CT are employees and shareholders of Incyte. IMS was an employee of Incyte at the time of the study. MG is a speaker for Guardant and a consultant for Cellularity, Merck, and Sanofi. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period., Patients and Methods: The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently., Conclusions: Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background/aim: Cholangiocarcinoma (CCA) is an aggressive tumor with limited treatment options especially in 2nd line or later treatments. Targeting fibroblast growth factor receptor (FGFR) 2 has recently emerged as a promising treatment option for patients with CCA harboring FGFR2-fusion. This study investigated the antitumor activities of tasurgratinib as an orally available FGFR1-3 inhibitor, in preclinical FGFR2-driven CCA models., Materials and Methods: Antitumor activities of tasurgratinib were examined in vitro and in vivo using NIH/3T3 cells expressing FGFR2-fusion as FGFR2-driven CCA models, and in vivo using a CCA patient-derived xenograft model. The molecular mechanism of action of tasurgratinib was elucidated through co-crystal structure analysis with FGFR1, manual complex model analysis with FGFR2, and binding kinetics analysis with FGFR2. Furthermore, the cell-based inhibitory activities against acquired resistant FGFR2 mutations in patients with CCA treated with FGFR inhibitors were evaluated., Results: Tasurgratinib showed antitumor activity in preclinical FGFR2-driven CCA models by inhibiting the FGFR signaling pathway in vitro and in vivo. Furthermore, cell-based target engagement assays indicated that tasurgratinib had potent inhibitory activities against FGFR2 mutations, such as N549H/K, which are the major acquired mutations in CCA. We also confirmed that tasurgratinib exhibited fast association and slow dissociation kinetics with FGFR2, binding to the ATP-binding site and the neighboring region, and adopting an Asp-Phe-Gly (DFG)-"in" conformation., Conclusion: These data demonstrate the therapeutic potential of tasurgratinib in FGFR2-driven CCA and provide molecular mechanistic insights into its unique inhibitory profile against secondary FGFR2 resistance mutations in patients with CCA treated with FGFR inhibitors., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Fibroblast Growth Factor Receptor Like 1 (FGFRL1) signaling has crucial role in a multitude of processes during genetic diseases, embryonic development and various types of cancer. Due to its partial structural similarity with its classical Fibroblast Growth Factor Receptor [FGFR] counterparts and lack of tyrosine kinase domain, FGFRL1 was thought to work as a decoy receptor in FGF/FGFR signaling. Later on, growing number evidences showed that expression of FGFRL1 affects major pathways like ERK1/2, Akt and others, which are dysfunctional in a wide range of human cancers. In this review, we provide an overview of the current understanding of FGFRL1 and its roles in cell differentiation, adhesion and proliferation pathways . Overexpression of FGFRL1 might lead to tumor progression and invasion. In this context, inhibitors for FGFRL1 might have therapeutic benefits in human cancer prognosis.

Bemarituzumab (FPA144) is a first-in-class, humanized, afucosylated immunoglobulin G1 monoclonal antibody (mAb) directed against fibroblast growth factor receptor 2b (FGFR2b) with two mechanisms of action against FGFR2b-overexpressing tumors: inhibition of FGFR2b signaling and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). Bemarituzumab is being developed as a cancer therapeutic, and we summarize here the key nonclinical data that supported moving it into clinical trials. Bemarituzumab displayed sub-nanomolar cross-species affinity for FGFR2b receptors, with >20-fold enhanced binding affinity to human Fc gamma receptor IIIa compared with the fucosylated version. In vitro, bemarituzumab induced potent ADCC against FGFR2b-expressing tumor cells, and inhibited FGFR2 phosphorylation and proliferation of SNU-16 gastric cancer cells in a concentration-dependent manner. In vivo, bemarituzumab inhibited tumor growth through inhibition of the FGFR2b pathway and/or ADCC in mouse models. Bemarituzumab demonstrated enhanced anti-tumor activity in combination with chemotherapy, and due to bemarituzumab-induced natural killer cell-dependent increase in programmed death-ligand 1, also resulted in enhanced anti-tumor activity when combined with an anti-programmed death-1 antibody. Repeat-dose toxicity studies established the highest non-severely-toxic dose at 1 and 100 mg/kg in rats and cynomolgus monkeys, respectively. In pharmacokinetic (PK) studies, bemarituzumab exposure increase was greater than dose-proportional, with the linear clearance in the expected dose range for a mAb. The PK data in cynomolgus monkeys were used to project bemarituzumab linear PK in humans, which were consistent with the observed human Phase 1 data. These key nonclinical studies facilitated the successful advancement of bemarituzumab into the clinic.

FGFR3 is a prognostic and predictive marker and is a validated therapeutic target in urothelial bladder cancer. Its utility as a marker and target in the context of immunotherapy is incompletely understood. We review the role of FGFR3 in bladder cancer and discuss preclinical and clinical clues of its effectiveness as a patient selection factor and therapeutic target in the era of immunotherapy.

Gastric cancer (GC) is the third leading cause among all cancer deaths globally. Although the treatment outcome of GC has improved, the survival of patients with GC at stages III and IV remains unsatisfactory. Among several types of GC, scirrhous type GC (SGC) shows highly aggressive growth and invasive activity, leading to frequent peritoneal metastasis. SGC is well known to accompany abundant stromal cells that compose the tumor microenvironment (TME) along with the produced extracellular matrix (ECM) and secreted factors. One of the main stromal components is cancer associated fibroblast (CAF). In the SGC microenvironment, CAFs are a source of various secreted factors, including fibroblast growth factors (FGFs), which mediate prominent tumor-stimulating activity. In turn, cancer cells also secrete numerous factors, which can activate and educate CAFs. Current findings suggest that cancer cells and stromal cells communicate interactively via the soluble factors, the ECM, and likely also by exosomes. In this review, we focus on the soluble factors mediating communication between cancer cells and CAFs in SGC, and consider how they are related to the modulation of TME and the high rate of peritoneal metastasis. At last, we discuss the perspectives on targeting these communication pathways for improved future treatment.

Abstract Background Thyroid dysfunction has not been previously reported in clinical trials of selective fibroblast growth factor receptor (FGFR) inhibitors including AZD4547. Herein, we report a case of worsening hypothyroidism in a patient with advanced urothelial cancer treated with AZD4547. Case presentation An 80-year-old Caucasian female with metastatic urothelial carcinoma failed first-line chemotherapy with gemcitabine and carboplatin and second-line treatment with atezolizumab, an inhibitor of programmed cell death ligand 1. She developed hypothyroidism at completion of atezolizumab treatment and responded to levothyroxine. Subsequently she was enrolled to a phase II study and received AZD4547 due to an actionable mutation at FGFR3 found in tumor biopsy. Two months later, she experienced recurrent hypothyroidism symptoms, and was hospitalized twice for small bowel obstruction. Her thyroid stimulating hormone level was significantly increased to 2957 uIU/mL (reference range 0.8–7.7 uIU/mL). Her levothyroxine dose was increased accordingly. Her thyroid function returned to normal 1 month afterwards, and small bowel obstruction did not recur. Conclusion Further reports and studies will be needed to confirm the relationship between AZD4547 and hypothyroidism. Based on this observation and possible mechanisms for thyroid dysfunction discussed in this paper, routine thyroid function monitoring in patients receiving FGFR inhibitor should be considered.

Abstract is missing (Short communication)

Advanced gastrointestinal stromal tumors (GIST) are typically treated with tyrosine kinase inhibitors, and imatinib is the most commonly used standard of care in first line treatments. The use of this and other tyrosine kinase inhibitors is associated with objective tumor responses and prolongation of progression-free and overall survival, but the treatment of metastatic disease is non-curative due to the selection or acquisition of secondary mutations and the activation of alternative kinase signaling pathways, leading to resistance and disease progression after an initial response. The present preclinical study evaluated the potential use of the fibroblast growth factor receptor inhibitors infigratinib and dovitinib alone or in combination with the mitogen-activated protein kinase inhibitor binimetinib in mouse models of GIST with different sensitivity or resistance to imatinib. Patient- and cell-line-derived GIST xenografts were established by bilateral, subcutaneous transplantation of human GIST tissue in female adult nu/nu NMRI mice. The mice were treated with dovitinib, infigratinib, or binimetinib, either alone or in combination with imatinib. The safety of treated animals was assessed by well-being inspection and body weight measurement. Antitumor effects were assessed by caliper-based tumor measurement. H&E staining and immunohistochemistry were used for assessing anti-mitotic and pro-apoptotic activity of the experimental treatments. Western blotting was used for assessing effects of the agents on kinase signaling pathways. Anti-angiogenic activity was assessed by measuring tumor vessel density. Dovitinib was found to have antitumor efficacy in GIST xenografts characterized by different imatinib resistance patterns. Dovitinib had better efficacy than imatinib (both at standard and increased dose) and was found to be well tolerated. Dovitinib had better efficacy in a KIT exon 9 mutant model, highlighting a role of patient selection in clinical GIST trials with the agent. In a model with KIT exon 11 and 17 mutations, dovitinib induced tumor necrosis, most likely due to anti-angiogenic effects. Additive effects combining dovitinib with binimetinib were limited.

Abstract Background Fibroblast growth factor (FGF)-2 plays a crucial role in the pathophysiology of cardiovascular diseases (CVDs). FGF-2 was reported to induce cardiac hypertrophy through activation of FGF receptor 1 (FGFR1). Multiple laboratory findings indicate that calcitriol may be a potential treatment for CVDs. In this study, we attempted to investigate whether calcitriol regulates FGFR1 expression to modulate the effects of FGF-2 signaling in cardiac myocytes and explored the potential regulatory mechanism. Methods Western blot, polymerase chain reaction, small interfering RNA, fluorometric activity assay, and chromatin immunoprecipitation (ChIP) analyses were used to evaluate FGFR1, FGFR2, FGFR3, FGFR4, phosphorylated extracellular signal-regulated kinase (p-ERK), β-myosin heavy chain (β-MHC), phosphorylated phospholipase Cγ (p-PLCγ), nuclear factor of activated T cells (NFAT), and histone deacetylase (HDAC) expressions and enzyme activities in HL-1 atrial myocytes without and with calcitriol (1 and 10 nM) treatment, in the absence and presence of FGF-2 (25 ng/mL) or suberanilohydroxamic acid (SAHA, a pan-HDAC inhibitor, 1 μM). Results We found that calcitriol-treated HL-1 cells had significantly reduced FGFR1 expression compared to control cells. In contrast, expressions of FGFR2, FGFR3, and FGFR4 were similar between calcitriol-treated and control HL-1 cells. FGF-2-treated HL-1 cells had similar PLCγ phosphorylation and nuclear/cytoplasmic NFAT expressions compared to control cells. FGF-2 induced lower expressions of p-ERK and β-MHC in calcitriol-treated HL-1 cells than in control cells. FGFR1-knockdown blocked FGF-2 signaling and reversed the protective effects of calcitriol. Compared to control cells, calcitriol-treated HL-1 cells had higher nuclear HDAC activity. The ChIP analysis demonstrated a significant decrease in acetyl-histone H4, which is associated with an increase in HDAC3 in the FGFR1 promoter. Calcitriol-mediated FGFR1 downregulation was attenuated in the presence of SAHA. Conclusions Calcitriol diminished FGFR1 expression through HDAC activation, which ameliorated the harmful effects of FGF-2 on cardiac myocytes.

Purpose: Fibroblast growth factor receptors (FGFR) and pathways are important players in breast cancer (BC) development. They are commonly altered, and BCs exhibiting FGFR gene amplification are currently being studied for drug development. Here, we aimed to compare the effects of three FGFR inhibitors (FGFRis), i.e., non-selective TKI258 and selective BGJ398 and AZD4547, on different BC-derived cell lines (BCCs) and primary tissues. Methods: The human BCCs MCF-7 and MDA-MB-231(SA) (wild-type FGFR) and MFM223 (amplified FGFR1 and FGFR2) were analyzed for FGFR expression using qRT-PCR, and the effects of FGFRis on FGFR signaling by Western blotting. The effects of FGFRis on proliferation, viability, migration and invasion of BCCs were assessed in 2D cultures using live-cell imaging, and in 3D cultures using phenotypic analysis of organoids. To study radio-sensitization, FGFRi treatment was combined with irradiation. Patient-derived BC samples were treated with FGFRis in explant cultures and immunostained for Ki67 and cleaved caspase 3. Results: We found that all FGFRis tested decreased the growth and viability of BC cells in 2D and 3D cultures. BGJ398 and AZD4547 were found to be potent at low concentrations in FGFR-amplified MFM233 cells, whereas higher concentrations were required in non-amplified MCF7 and MDA-MB-231(SA) cells. TKI258 inhibited the migration and invasion, whereas BGJ398 and AZD4547 only inhibited the invasion of MDA-MB-231(SA) cells. FGFRi treatment of MCF7 and MFM223 cells enhanced the inhibitory effect of radiotherapy, but this effect was not observed in MDA-MB-231(SA) cells. FGFRi-treated primary BC explants with moderate FGFR levels showed a tendency towards decreased proliferation and increased apoptosis. Conclusions: Our results indicate that, besides targeting FGFR-amplified BCs with selective FGFRis, also BCs without FGFR amplification/activation may benefit from FGFRi-treatment. Combination with other treatment modalities, such as radiotherapy, may allow the use of FGFRis at relatively low concentrations and, thereby, contribute to better BC treatment outcomes. [ABSTRACT FROM AUTHOR]

Pfeiffer syndrome (PS) is a rare autosomal dominant craniofacial disorder characterized by primary craniosynostosis, midface hypoplasia, and extremities' abnormalities including syndactyly. The purpose of this article was to review the current knowledge regarding how PS affects the nervous system. Methodologically, we conducted a systematic review of the existing literature concerning involvement of the nervous system in PS. Multiple-suture synostosis is common, and it is the premature fusion and abnormal growth of the facial skeleton's bones that cause the characteristic facial features of these patients. Brain abnormalities in PS can be primary or secondary. Primary anomalies are specific developmental brain defects including disorders of the white matter. Secondary anomalies are the result of skull deformity and include intracranial hypertension, hydrocephalus, and Chiari type I malformation. Spinal anomalies in PS patients include fusion of vertebrae, "butterfly" vertebra, and sacrococcygeal extension. Different features have been observed in different types of this syndrome. Cloverleaf skull deformity characterizes PS type II. The main neurological abnormalities are mental retardation, learning difficulties, and seizures. The tricky neurological examination in severely affected patients makes difficult the early diagnosis of neurological and neurosurgical complications. Prenatal diagnosis of PS is possible either molecularly or by sonography, and the differential diagnosis includes other craniosynostosis syndromes. Knowing how PS affects the nervous system is important, not only for understanding its pathogenesis and determining its prognosis but also for the guidance of decision-making in the various critical steps of its management. The latter necessitates an experienced multidisciplinary team. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor (FGFR) tyrosine kinases, which are expressed on the cell membrane, are involved in a wide range of biological functions such as cell proliferation, survival, migration, and differentiation. The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of several selective FGFR inhibitors for use in these indications, for example, infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib. In addition to the typical adverse events associated with tyrosine kinases, the FGFR inhibitors appear to give rise to a number of adverse events affecting the skin. Here we describe these skin events, which include the more common nail adverse events (e.g., onycholysis), palmar–plantar erythrodysesthesia syndrome, and stomatitis, as well as less common reactions such as calciphylaxis. This review aims to provide oncologists with an understanding of these dermatologic events and proposes guidelines for the management of treatment‐emergent dermatologic adverse events. Awareness of possible adverse events associated with specific drugs should allow physicians to educate patients as to what to expect and implement effective management plans at the earliest possible opportunity, thereby preventing premature discontinuation while maintaining patient quality of life. Implications for Practice: Identification of fibroblast growth factor receptor (FGFR) aberrations in cholangiocarcinoma and bladder cancer led to development of selective FGFR inhibitors for these indications, based on clinical benefit and safety profiles. The most frequent adverse events (AEs) include those affecting skin, hair, and nails, a unique class effect of these agents. These are usually mild to moderate in severity. This work reviewed skin AEs reported with FGFR inhibitors and provides management guidelines for physicians, aiming to increase awareness of skin events and provide effective treatment strategies. Early intervention and effective management may improve treatment adherence, optimize outcomes, and improve quality of life. This review provides oncologists with an understanding of dermatologic adverse events related to the use of FGFR inhibitors and proposes guidelines for treatment. [ABSTRACT FROM AUTHOR]

Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition. To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC. Oral infigratinib 125 mg/d for 21 d every 28 d. Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed. Clinical outcomes were compared in groups with/without hyperphosphatemia. Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4–48.4) versus 5.3% (95% CI 0.1–26.0); disease control rate 75.0% (95% CI 60.4–86.4) versus 36.8% (95% CI 16.3–61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size. This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial. Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies. Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies. [ABSTRACT FROM AUTHOR]

• Agents targeting angiogenic pathways such as bevacizumab have demonstrated efficacy in mesothelioma. An analysis of the combination of stromal and vascular biomarkers is relevant to the use of multi-angiokinase targets of PDGF, FGF and VEGF in malignant mesothelioma to help determine their prognostic implications. • High CD31 was an independent poor prognostic factor and high PDGF-CC expression was associated with poor survival in mesothelioma. • There was a high incidence of positive VEGF and FGFR IHC in the large mesothelioma cohort but no significant correlation between prognosis and immune expression was found. Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other mesothelial membranes. Agents targeting vascular endothelial growth factor (VEGF) such as bevacizumab; and multi-kinase inhibitors such as nintedanib [angiokinase inhibitor of VEGF, platelet-derived growth factor (PDGF) receptor and fibroblast growth factor receptor (FGFR)] have recently demonstrated efficacy in MM. Tissue microarrays (TMAs) were created from formalin-fixed, paraffin-embedded tissue samples obtained from 326 patients with MM who were treated surgically. PDGF-CC, FGFR-1, VEGF and CD31 expression were analysed by immunohistochemical (IHC) staining. The H-score method assigned a score of 0–300 to each sample, based on the percentage of cells stained at different intensities. CD31 was evaluated via Chalkley's method to evaluate microvessel density. We evaluated the association between expression of the biomarkers, clinicopathological factors and outcomes, in patients with MM. CD31 high (≥5) was seen in only 31/302 (10.3%) irrespective of histology. PDGF-CC high (≥150) was seen in 203 /310 (65%) of all samples. VEGF high (≥80) was seen in 219/322 (68%) of all MM with 143/209 (68%) of epithelioid histology. FGFR-1 high (≥40) was seen in 127/310 (41%) of all MM. There was no association of VEGF and FGFR-1 IHC with survival nor differences between histological subtypes. There was a non-significant trend towards poorer survival in epithelioid tumours with increased PDGF-CC expression (OS 18.5 vs 13.2 months; HR 0.7928; 95% CI 0.5958 to 1.055, P = 0.1110). High CD31 score was associated with significantly poorer survival (OS 12 vs 8.6 months; HR 0.48; 95% CI 0.2873 to 0.7941, P = 0.0044). Of the 31 patients with high CD31 scores; 23/31 (74%) were also high for PDGF-CC and 20/31 (64%) with high VEGF scores. CD31 was found to be an independent prognostic factor in multivariate analysis (HR 1.540; 95% CI 1.018 to 2.330; p = 0.041). High CD31 was an independent poor prognostic factor and high PDGF-CC expression was associated with poor survival in MM. Abrogating these pathways may have prognostic implications. [ABSTRACT FROM AUTHOR]

FGFR3 is a prognostic and predictive marker and is a validated therapeutic target in urothelial bladder cancer. Its utility as a marker and target in the context of immunotherapy is incompletely understood. We review the role of FGFR3 in bladder cancer and discuss preclinical and clinical clues of its effectiveness as a patient selection factor and therapeutic target in the era of immunotherapy. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the third leading cause among all cancer deaths globally. Although the treatment outcome of GC has improved, the survival of patients with GC at stages III and IV remains unsatisfactory. Among several types of GC, scirrhous type GC (SGC) shows highly aggressive growth and invasive activity, leading to frequent peritoneal metastasis. SGC is well known to accompany abundant stromal cells that compose the tumor microenvironment (TME) along with the produced extracellular matrix (ECM) and secreted factors. One of the main stromal components is cancer associated fibroblast (CAF). In the SGC microenvironment, CAFs are a source of various secreted factors, including fibroblast growth factors (FGFs), which mediate prominent tumor-stimulating activity. In turn, cancer cells also secrete numerous factors, which can activate and educate CAFs. Current findings suggest that cancer cells and stromal cells communicate interactively via the soluble factors, the ECM, and likely also by exosomes. In this review, we focus on the soluble factors mediating communication between cancer cells and CAFs in SGC, and consider how they are related to the modulation of TME and the high rate of peritoneal metastasis. At last, we discuss the perspectives on targeting these communication pathways for improved future treatment. [ABSTRACT FROM AUTHOR]

The Hippo signaling pathway regulates cell proliferation and organ growth, and its activation is mainly reflected by the phosphorylation levels of Yes-associated protein (YAP). In this study, we show that YAP facilitates embryonic neural stem cell proliferation by elevating their responsiveness to fibroblast growth factor 2 (FGF2), one of the major growth factors for neural stem cells, in vivo as well as in vitro. Western blot and quantitative real-time PCR analyses revealed that expression of the FGF receptors (FGFRs) FGFR1 to FGFR4 were greatly increased by YAP expression upon FGF2 treatment, followed by upregulation of the mitogen-activated protein kinase and protein kinase B signaling pathways. Furthermore, as assessed by quantitative real-time PCR analyses, YAP-induced FGFR expression was found to be TEA domain transcription factor (TEAD)-independent, and transcriptional coactivator with PDZ-binding motif, the other homolog of Yorki in the Drosophila Hippo signaling pathway, was found to possess similar activity to YAP. Finally, adjustment of FGFR signaling activity in the YAP-expressing cells to control levels efficiently offset the cell proliferative effects of YAP, suggesting that the increased proliferation of YAP-expressing neural stem cells was mainly attributable to enhanced FGFR signaling. Our data indicate that YAP plays an important role in neural stem cell regulation by elevating FGFR expression, subsequently leading to enhanced cell proliferation. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a refractory cancer with limited treatment options and poorly understood molecular mechanisms underlying tumor development. The most effective treatment is surgical resection; however, patients are highly prone to recurrence. Moreover, considering that most patients are diagnosed in advanced stages, treatment options are restricted to palliative care, which results in poor prognosis. Due to the limited effect of chemotherapy and radiotherapy, targeted therapy is becoming a hot topic in the field of biliary cancer treatment. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway involves a variety of key biological processes for cell survival, differentiation, and metabolism. Next-generation sequencing data mining has shown that high levels of FGF/FGFR expression are associated with reduced overall survival (OS) in CAA, which indicates that the FGF/FGFR pathway may be an effective target for CAA treatment. This paper reviews the effect of FGF/FGFR signaling on CCA from onset to treatment and highlights the promise of FGF/FGFR signaling pathway inhibitors for targeting CCA. [ABSTRACT FROM AUTHOR]

Crouzon syndrome (CS) is a rare autosomal dominant inherited disorder caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. The disease is characterized by premature fusion of the coronal and sagittal sutures of the skull, resulting in clinical manifestations of midfacial hypoplasia, shallow orbit, maxillary dysplasia, and occasional upper respiratory obstruction. This article presents the case of a child aged 2 years and 7 months with CS scheduled for bilateral tonsillectomy and adenoidectomy. The patient had a difficult procedure of extubation and was reintubated and the tracheal intubation was removed 2 days after surgery. The CS is a rare condition with physical characteristics that can result in difficult airway manipulation. It is important for anesthesiologists to recognize and avoid potential airway complications in the management of such patients through detailed preoperative evaluation and careful observation after surgery to reduce perioperative risks. [ABSTRACT FROM AUTHOR]

FgfrL1 is a novel growth factor receptor that is primarily expressed in musculoskeletal tissues and the kidney. FgfrL1-deficient mice have a malformed diaphragm and no kidneys. Such animals die immediately after birth because they are not able to inflate their lungs. The FgfrL1 molecule is composed of three extracellular Ig domains, a transmembrane helix and a short intracellular domain. To investigate the contribution of each of these domains to the function of the novel receptor, we generated mice with deletions of the individual domains. Mice lacking the intracellular domain are viable and phenotypically normal. Mice lacking the first (N-terminal) Ig domain are also viable and normal, but have a reduced life span. Mice lacking the Ig2 or the Ig3 domain are born alive, but die within 24 ​h after birth. Ig2-deficient animals exhibit substantially smaller kidneys than wild-type littermates and contain a lower number of glomeruli. Ig3-deficient mice completely lack metanephric kidneys. Interestingly, both the Ig2 and the Ig3-deficient animals show only minor alterations in the diaphragm, which still enables them to inflate their lungs after birth. Our results demonstrate that the principal function of the FgfrL1 receptor is to control the growth of the metanephric kidneys by regulating nephrogenesis. It appears that this function is primarily accomplished by the Ig3 domain with some contribution of the Ig2 domain. It is conceivable that the two domains interact with an Fgf ligand and another molecule from the surface of neighboring cells to induce condensation of the metanephric mesenchyme to renal epithelia and glomeruli. • Receptor FgfrL1 contains 3 extracellular Ig domains and an intracellular tail. • Ig1-deficient mice are normal but have a reduced life span. • Ig2-deficient mice have smaller kidneys and die within 24 ​h after birth. • Ig3-deficient animals have no kidneys and die within 24 ​h after birth. • Thus, FgfrL1 primarily controls nephrogenesis and the Ig3 domain is most important. [ABSTRACT FROM AUTHOR]

Purpose: Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC). Methods: We investigated FGFR4 expression in patients with ATC and analyzed their clinical responses to lenvatinib. Primary tumor samples were obtained from 12 patients with ATC who underwent surgery or core needle biopsy. FGFR4 protein expression in all ATC samples was analyzed via immunohistochemistry, and the treatment efficacy of lenvatinib was evaluated. Results: The proportion of FGFR4-positive cells in the samples ranged from 0 to 50%. Four patients had partial responses, and three patients had stable diseases as a best clinical response to lenvatinib. The median PFS durations of patients with none, weak, and moderate intensity were 0.5, 3.2 (95% CI 1.1–not estimable [NE]), and 4.6 (95% CI 1.1–NE) months, respectively (p = 0.003). Conclusions: Because FGFR4 was expressed in ATC tissues, the FGFR4 expression might be associated with the treatment efficacy of lenvatinib in a part of ATC patients. To clarify whether FGFR4 can serve as a prognostic or predictive factor for lenvatinib therapy, more cases must be accumulated. [ABSTRACT FROM AUTHOR]

Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by tumor cell microemboli with occlusive fibrointimal remodeling in small pulmonary vessels. Platelet-derived growth factor (PDGF) has been implicated in the development of PTTM, and fibroblast growth factor (FGF) promotes PDGF signaling via PDGF receptor β. We here describe a cancer patient who presented with dyspnea of uncertain etiology and whose condition worsened rapidly. A 68-year-old man with hypopharyngeal squamous cell carcinoma (cT4aN2bM0, stage IVA) was treated with surgery followed by radiation. Two years later, a lung metastatic lesion was surgically removed on the basis of suspected primary lung cancer. The patient was thereafter monitored without chemotherapy. Two months later, he had third-degree burns and received conservative therapy including debridement and application of trafermin (FGF2) spray. Two weeks later, he was hospitalized with complaints of fever and dyspnea. Pneumonia and pulmonary embolism were ruled out by chest computed tomography with pulmonary arterio-graphy, whereas intravascular lymphoma was excluded by laboratory testing. Malignant cells were detected in his peripheral blood on hospital day 8, and their number increased gradually thereafter. His respiratory symptoms worsened, and the patient died on hospital day 10. We concluded that the cause of death was PTTM, with the clinical course suggesting a possible relation to trafermin. This suggestion was supported by the detection of FGF receptor 2 overexpression in the primary tumor by immunostaining. [ABSTRACT FROM AUTHOR]

Alveolar epithelial cell (AEC) injury is central to the pathogenesis of pulmonary fibrosis. Epithelial FGF (fibroblast growth factor) signaling is essential for recovery from hyperoxia- and influenzainduced lung injury, and treatment with FGFs is protective in experimental lung injury. The cell types involved in the protective effect of FGFs are not known. We hypothesized that FGF signaling in type II AECs (AEC2s) is critical in bleomycin-induced lung injury and fibrosis. To test this hypothesis, we generated mice with tamoxifeninducible deletion of FGFR1-3 (fibroblast growth factor receptors 1, 2, and 3) in surfactant protein C-positive (SPC1) AEC2s (SPC triple conditional knockout [SPC-TCKO]). In the absence of injury, SPCTCKO mice had fewer AEC2s, decreased Sftpc (surfactant protein C gene) expression, increased alveolar diameter, and increased collagen deposition. After intratracheal bleomycin administration, SPCTCKO mice had increased mortality, lung edema, and BAL total protein, and flow cytometry and immunofluorescence revealed a loss of AEC2s. To reduce mortality of SPC-TCKO mice to less than 50%, a 25-fold dose reduction of bleomycin was required. Surviving bleomycin-injured SPC-TCKO mice had increased collagen deposition, fibrosis, and ACTA2 expression and decreased epithelial gene expression. Inducible inactivation of individual Fgfr2 or Fgfr3 revealed that Fgfr2, but not Fgfr3, was responsible for the increased mortality and lung injury after bleomycin administration. In conclusion, AEC2-specific FGFR2 is critical for survival in response to bleomycin-induced lung injury. These data also suggest that a population of SPC1 AEC2s require FGFR2 signaling for maintenance in the adult lung. Preventing epithelial FGFR inhibition and/or activating FGFRs in alveolar epithelium may therefore represent a novel approach to treating lung injury and reducing fibrosis. [ABSTRACT FROM AUTHOR]

• Intrahepatic cholangiocarcinoma (ICC), a subset of primary liver cancer, is one of the most lethal cancers with very limited treatment options. • Aberrant activation of a number of molecular pathways drives ICC pathogenesis. • Chromosomal translocations with Fibroblast Growth Factor Receptor 2 (FGFR2) – a Receptor Tyrosine Kinase – have been identified as drivers in ICC. • Structural comparisons of FGFR2 translocations and molecular signaling pathways are presented, together with therapeutic approaches. • This review presents the unifying features of oncogenic FGFR2 translocations and the current landscape of TKIs in clinical trials for ICC patients. Cholangiocarcinoma, originating from the biliary duct, represents a subset of liver cancer. With about 8000 new cases of cholangiocarcinoma diagnosed annually in the U.S., these fall into three categories: intrahepatic, peri-hilar, and extrahepatic cholangiocarcinoma. Arising from the epithelium of the bile duct, intrahepatic cholangiocarcinoma (ICC) is a universally fatal malignancy with very few treatment options. The poor prognosis and lack of molecular targeted therapies highlights ICC as a critical unmet medical need. With advances in sequencing technology, numerous chromosomal translocations have been discovered as drivers in cancer initiation and progression. Particularly in ICC, chromosomal translocations involving Fibroblast Growth Factor Receptor 2 (FGFR2) have been frequently identified, resulting in the creation of oncogenic fusion proteins. At the N-terminus, these fusion proteins share a nearly-identical FGFR2 moiety retaining an intact kinase domain and, at the C-terminus, a dimerization/oligomerization domain provided by different partner genes, including: Periphilin 1 (PPHLN1), Bicaudal family RNA binding protein 1 (BICC1), Adenosylhomocysteinase Like 1 (AHCYL1), and Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3). A number of pre-clinical and clinical trials have shown the effectiveness of FGFR inhibitors in treating FGFR2 fusion-positive ICC patients. However, the efficacy of these inhibitors may be short-lived due to acquired resistance. In this review, we provide an overview of FGFR2 fusions, comparing their structures and mechanism of dimerization, examining the importance of FGFR2 as a partner gene, as well as highlighting the significance of alternative splicing of FGFR2 in these fusion proteins. In addition, we discuss various therapeutic options and their associated potencies in targeting these translocation-induced ICCs. [ABSTRACT FROM AUTHOR]

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single‐ and multiple‐dose administration, to understand clinically relevant covariates, and to quantify the inter‐ and intraindividual variability in erdafitinib PK. An open, linear, 3‐compartment disposition model with first‐order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent. After oral administration, erdafitinib was rapidly absorbed, with a time to maximum concentration between 2 and 4 hours. In patients, erdafitinib total apparent oral clearance was 0.200 L/h (median free fraction = 0.24%), and the effective terminal half‐life of total drug was 76.4 hours. Interindividual variability in PK parameters was moderate for oral clearance and central volume of distribution, and large for absorption rate and peripheral volume of distribution. Sex and renal function were significant covariates on free oral clearance, while weight, sex, and α1‐acid‐glycoprotein were significant on oral central volume of distribution. Age, race, and mild hepatic impairment were not significant covariates of erdafitinib exposure. Given that the magnitude of the covariate effects were within 25% of reference values and that the recommended dosing regimen of erdafitinib comprises individual dose up‐titrations and reductions based on presence or absence of toxicities, the clinical relevance of the investigated covariates is expected to be limited, and no dose adjustments are warranted. [ABSTRACT FROM AUTHOR]

Summary: ASP5878 is a selective small-molecule inhibitor of fibroblast growth factor receptors (FGFRs). This study investigated safety, tolerability, and antitumor effect of single and multiple oral doses of ASP5878 in patients with solid tumors. This phase 1, open label, first-in-human study comprised dose-escalation and dose-expansion parts. Primary objectives of the dose-escalation part were to identify the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended dose of ASP5878 for the dose-expansion part. Nine dose cohorts of ASP5878 were evaluated (0.5─2 mg once daily; 2─40 mg twice daily [BID]). A single dose of ASP5878 was followed by a 2-day pharmacokinetic collection, and then either 28-day cycles of daily dosing (ASP5878 ≤ 10 mg BID) or 5-day dosing/2-day interruption (ASP5878 ≥ 20 mg BID). The primary objective of the dose-expansion part was to determine the safety of ASP5878 (16 mg BID) administered in 28-day cycles of 5-day dosing/2-day interruption in patients with urothelial carcinoma, hepatocellular carcinoma, or squamous cell lung carcinoma with FGFR genetic alterations. Safety was assessed by monitoring adverse events (AEs). Thirty-five patients were enrolled and 31 discontinued in the dose-escalation part; 51 patients were enrolled and 51 discontinued in the dose-expansion part. In the dose-escalation part, 66.7% of patients in the 20 mg BID 5-day dosing/2-day interruption group reported DLTs of hyperphosphatemia. The recommended dose for the dose-expansion part was 16 mg BID. Common AEs included retinal detachment, diarrhea, and increased alanine aminotransferase. One death occurred that was not related to ASP5878. ASP5878 was well tolerated with manageable toxicities including hyperphosphatemia. [ABSTRACT FROM AUTHOR]

Copyright of Wiener Medizinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Periampullary cancers (PAC) including pancreatic, ampulla of Vater (AOV), and common bile duct (CBD) cancers are highly aggressive with a lack of useful prognostic markers beyond T stage. However, T staging can be biased due to the anatomic complexity of this region. Recently, several markers related to cancer stem cells and epithelial-mesenchymal transition (EMT) such as octamer transcription factor-4 (Oct4) and fibroblast growth factor receptor 1 (FGFR1) respectively, have been proposed as new promising markers in other solid cancers. The aim of this study was to assess the expression and prognostic significance of stem cell/EMT markers in PACs.Methods: Formalin-fixed, paraffin-embedded tissues of surgically excised PACs from the laboratory archives from 1998 to 2014 were evaluated by immunohistochemical staining for stem cell/EMT markers using tissue microarray. The clinicopathologic parameters were documented and statistically analyzed with the immunohistochemical findings. Survival and recurrence data were collected and analyzed.Results: A total of 126 PAC cases were evaluated. The average age was 63 years, with 76 male and 50 female patient samples. Age less than 74 years, AOV cancers, lower T & N stage, lower tumor size, no lymphatic, vascular, perineural invasion and histologic well differentiation, intestinal type, no fibrosis, severe inflammation were significantly associated with the better overall survival High expression levels of FGFR1 as well as CK20, CDX2, and VEGF were significantly related to better overall survival, while other stem cell markers were not related. Similar findings were observed for tumor recurrence using disease-free survival.Conclusions: In addition to other clinicopathologic parameters, severe fibrosis was related to frequent tumor recurrence, and high FGFR1 expression was associated with better overall survival. Histologic changes such as extensive fibrosis need to be investigated further in relation to EMT of PACs. [ABSTRACT FROM AUTHOR]

Introduction: Craniosynostosis (CS) syndrome is an autosomal dominant condition (ADC) classically combining with CS and nonsyndromic CS (NSCS) including digital anomalies of the hands and feet. The majority of cases caused by a heterozygous mutation (HM) in the third immunoglobulin-like domain (IgIII) of fibroblast growth factor receptor (FGFR) 2 mutations outside this region of the protein.Material and Methods: We tried to find out the spectrum of genes involved in CS syndrome caused by the heterozygous missense mutation, the IgII and IgIII of FGFR2. FGFR3, FGFR4, TWIST, and MSX genes were performed and verified through the Indian population with CS children.Results: We find out that at conserved linker region (LR), the changes occurred among the larger families. Independent genetic origins, but phenotypic similarities add to the evidence supporting the theory of selfish spermatogonial selective advantage for this rare gain-of-function FGFR2 mutation. Polygenic novel mutation in both syndromic and nonsyndromic cases of CS promotes the translational research and holds a great promise to reproduce the molecular-based therapy and treatment as well. In this article, we summarized that genes involved in CS as evidence-based approach for characterization, identification, gene expression, and tissue engineering. We also described other related genes and proteins for the CS involvement and improvement of the diseases progression.Conclusion: HM again repeated the old story for both groups of syndromic CS and NSCS of Asian Indian children. Here, for the first time, we clearly reported that IgIII of FGFR2 mutations outside this region of the protein and tyrosine kinase (TK1 and TK2) responsible for both in molecular and cellular level for CS. It adds an evidence for future molecular targeting therapy to repair CS. [ABSTRACT FROM AUTHOR]

Background and Aim: Antioxidants are compounds that protect cells from attacks of free radicals. Lack of balance between antioxidants and free radicals results in oxidative stress, which ultimately results in cell damage. The effects of flavonoids are not related solely to their antioxidant properties, but also to their effects on cellular signal pathways. The present study was conducted to evaluate the effect of Quercetin on the structure of the third region of FGFR2b kinase using fluorescence method. Materials and Methods: Using SDS-PAGE, expression of the protein was determined and its constant concentration was used in the present study. Using different concentrations of Quercetin in the presence of a constant concentration of pure protein, the fluorescence spectrum and chemical denaturation were evaluated. Results: In the last studies, SDS-PAGE analysis of the purified proteins had confirmed that no contamination and unwanted bacterial proteins were co-eluted with the protein. Studying the spectrum of various concentrations of Quercetin in the presence of constant concentration of proteins showed a decrease in the intensity of the release; and also, the chemical denaturation changed the third structure of the kinase domain. Conclusion: The tertiary structural change of FGFR2b kinase domain represents a conformational change that may have a critical role in signal transduction cascade. Thus, this molecular transduction inconsistency can lead to cellular transduction complication; and as a result, inhibit the development and multiplication of cancerous cells.

Dietary phosphorus oversupply wastes non-renewable natural resources and raises environmental concerns in animal agriculture. We hypothesized that laying hens do not need large safety margins for dietary phosphorus because of the existence of fibroblast growth factor 23 (FGF23). In experiment 1, a total of 504 Hy-Line Brown laying hens (40-week-old) were randomly assigned to seven diets (for each diet, six replicates of 12 hens), containing 0.12, 0.17, 0.22, 0.27, 0.32, 0.37, and 0.42% non-phytate phosphorus, respectively, for 15 weeks. In experiment 2, a total of 14 Hy-Line Brown laying hens (40-week-old) were randomly assigned to two diets: (1) phosphorus restricted (n = 7) diet containing 0.14% non-phytate phosphorus, and (2) regular phosphorus (n = 7) diet containing 0.32% non-phytate phosphorus, for 21 days. Laying performance and egg quality were investigated in experiments 1 and 2. Phosphorus excretion and physiological changes were determined in experiment 2. It was found that dietary non-phytate phosphorus levels had no effects (P > 0.05) on laying performance and egg quality in either experiment. In experiment 2, laying hens fed 0.14% non-phytate phosphorus had decreased phosphorus excretion (by 52.6%, P < 0.001) when compared to those fed 0.32% non-phytate phosphorus. In response to the 0.14% non-phytate phosphorus diet, laying hens in experiment 2 exhibited: (1) suppressed calvaria mRNA expressions of FGF23 (by 57.8%, P < 0.001) and fibroblast growth factor receptor 1 (FGFR1, by 52.8%, P = 0.012), (2) decreased serum levels of FGF23 (by 41.7%, P = 0.011) and phosphorus (by 40.3%, P < 0.001), (3) decreased kidney mRNA expressions of FGFR1 (by 66.0%, P = 0.040) and FGFR4 (by 63.3%, P = 0.012) and decreased kidney protein expression of type 2a sodium-phosphorus co-transporter (NPt2a, by 51%, P = 0.025), (4) increased duodenum protein expression of NPt2b (by 45%, P = 0.032), and (5) increased excretion of calcium (by 22.9%, P ≤ 0.024). Collectively, decreasing dietary non-phytate phosphorus by up to 0.12% had no negative effects on egg-production performance but significantly decreased phosphorus excretion in laying hens. The laying hens adjusted to low-phosphorus diets by increasing intestinal NPt2b protein production, which was associated with decreased serum FGF23 concentration. Decreasing dietary non-phytate phosphorus is suggested to laying-hen nutritionists.

Fibroblast growth factor 2 (FGF2) plays important roles in tissue development and repair. Using heparan sulfates (HS)/heparin as a cofactor, FGF2 binds to FGF receptor (FGFR) and induces downstream signaling pathways, such as ERK pathway, that regulate cellular behavior. In most cell lines, FGF2 signaling displays biphasic dose-response profile, reaching maximal response to intermediate concentrations, but weak response to high levels of FGF2. Recent reports demonstrated that the biphasic cellular response results from competition between binding of FGF2 to HS and FGFR that impinge upon ERK signaling dynamics. However, the role of HS/heparin in FGF signaling has been controversial. Several studies suggested that heparin is not required for FGF-FGFR complex formation and that the main role of heparin is to protect FGF from degradation. In this study, we investigated the relationship between FGF2 stability, heparin dependence and ERK signaling dynamics using FGF2 variants with increased thermal stability (FGF2-STABs). FGF2-STABs showed higher efficiency in induction of FGFR-mediated proliferation, lower affinity to heparin and were less dependent on heparin than wild-type FGF2 (FGF2-wt) for induction of FGFR-mediated mitogenic response. Interestingly, in primary mammary fibroblasts, FGF2-wt displayed a sigmoidal dose-response profile, while FGF2-STABs showed a biphasic response. Moreover, at low concentrations, FGF2-STABs induced ERK signaling more potently and displayed a faster dynamics of full ERK activation and higher amplitudes of ERK signaling than FGF2-wt. Our results suggest that FGF2 stability and heparin dependence are important factors in FGF-FGFR signaling complex assembly and ERK signaling dynamics.

Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1-4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low-grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1-ITD-harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.

Dietary phosphorus oversupply wastes non-renewable natural resources and raises environmental concerns in animal agriculture. We hypothesized that laying hens do not need large safety margins for dietary phosphorus because of the existence of fibroblast growth factor 23 (FGF23). In experiment 1, a total of 504 Hy-Line Brown laying hens (40-week-old) were randomly assigned to seven diets (for each diet, six replicates of 12 hens), containing 0.12, 0.17, 0.22, 0.27, 0.32, 0.37, and 0.42% non-phytate phosphorus, respectively, for 15 weeks. In experiment 2, a total of 14 Hy-Line Brown laying hens (40-week-old) were randomly assigned to two diets: (1) phosphorus restricted (n = 7) diet containing 0.14% non-phytate phosphorus, and (2) regular phosphorus (n = 7) diet containing 0.32% non-phytate phosphorus, for 21 days. Laying performance and egg quality were investigated in experiments 1 and 2. Phosphorus excretion and physiological changes were determined in experiment 2. It was found that dietary non-phytate phosphorus levels had no effects (P > 0.05) on laying performance and egg quality in either experiment. In experiment 2, laying hens fed 0.14% non-phytate phosphorus had decreased phosphorus excretion (by 52.6%, P < 0.001) when compared to those fed 0.32% non-phytate phosphorus. In response to the 0.14% non-phytate phosphorus diet, laying hens in experiment 2 exhibited: (1) suppressed calvaria mRNA expressions of FGF23 (by 57.8%, P < 0.001) and fibroblast growth factor receptor 1 (FGFR1 , by 52.8%, P = 0.012), (2) decreased serum levels of FGF23 (by 41.7%, P = 0.011) and phosphorus (by 40.3%, P < 0.001), (3) decreased kidney mRNA expressions of FGFR1 (by 66.0%, P = 0.040) and FGFR4 (by 63.3%, P = 0.012) and decreased kidney protein expression of type 2a sodium-phosphorus co-transporter (NPt2a, by 51%, P = 0.025), (4) increased duodenum protein expression of NPt2b (by 45%, P = 0.032), and (5) increased excretion of calcium (by 22.9%, P ≤ 0.024). Collectively, decreasing dietary non-phytate phosphorus by up to 0.12% had no negative effects on egg-production performance but significantly decreased phosphorus excretion in laying hens. The laying hens adjusted to low-phosphorus diets by increasing intestinal NPt2b protein production, which was associated with decreased serum FGF23 concentration. Decreasing dietary non-phytate phosphorus is suggested to laying-hen nutritionists. [ABSTRACT FROM AUTHOR]

Background: Triple negative breast cancer (TNBC) accounts for 16% of breast cancers and represents an aggressive subtype that lacks targeted therapeutic options. In this study, mass spectrometry (MS)-based tyrosine phosphorylation profiling identified aberrant FGFR3 activation in a subset of TNBC cell lines. This kinase was therefore evaluated as a potential therapeutic target. Methods: MS-based tyrosine phosphorylation profiling was undertaken across a panel of 24 TNBC cell lines. Immunoprecipitation and Western blot were used to further characterize FGFR3 phosphorylation. Indirect immunofluorescence and confocal microscopy were used to determine FGFR3 localization. The selective FGFR1–3 inhibitor, PD173074 and siRNA knockdowns were used to characterize the functional role of FGFR3 in vitro. The TCGA and Metabric breast cancer datasets were interrogated to identify FGFR3 alterations and how they relate to breast cancer subtype and overall patient survival. Results: High FGFR3 expression and phosphorylation were detected in SUM185PE cells, which harbor a FGFR3-TACC3 gene fusion. Low FGFR3 phosphorylation was detected in CAL51, MFM-223 and MDA-MB-231 cells. In SUM185PE cells, the FGFR3-TACC3 fusion protein contributed the majority of phosphorylated FGFR3, and largely localized to the cytoplasm and plasma membrane, with staining at the mitotic spindle in a small subset of cells. Knockdown of the FGFR3-TACC3 fusion and wildtype FGFR3 in SUM185PE cells decreased FRS2, AKT and ERK phosphorylation, and induced cell death. Knockdown of wildtype FGFR3 resulted in only a trend for decreased proliferation. PD173074 significantly decreased FRS2, AKT and ERK activation, and reduced SUM185PE cell proliferation. Cyclin A and pRb were also decreased in the presence of PD173074, while cleaved PARP was increased, indicating cell cycle arrest in G1 phase and apoptosis. Knockdown of FGFR3 in CAL51, MFM-223 and MDA-MB-231 cells had no significant effect on cell proliferation. Interrogation of public datasets revealed that increased FGFR3 expression in breast cancer was significantly associated with reduced overall survival, and that potentially oncogenic FGFR3 alterations (eg mutation and amplification) occur in the TNBC/basal, luminal A and luminal B subtypes, but are rare. Conclusions: These results indicate that targeting FGFR3 may represent a therapeutic option for TNBC, but only for patients with oncogenic FGFR3 alterations, such as the FGFR3-TACC3 fusion. Video abstract. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is chronic and irreversible damage to the lung characterized by fibroblast activation and matrix deposition. Although recently approved novel anti‐fibrotic agents can improve the lung function and survival of patients with PF, the overall outcomes remain poor. In this study, a novel imidazopurine compound, 3‐(2‐chloro‐6‐fluorobenzyl)‐1,6,7‐trimethyl‐1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione (IM‐1918), markedly inhibited transforming growth factor (TGF)‐β‐stimulated reporter activity and reduced the expression of representative fibrotic markers, such as connective tissue growth factor, fibronectin, collagen and α‐smooth muscle actin, on human lung fibroblasts. However, IM‐1918 neither decreased Smad‐2 and Smad‐3 nor affected p38MAPK and JNK. Instead, IM‐1918 reduced Akt and extracellular signal‐regulated kinase 1/2 phosphorylation increased by TGF‐β. Additionally, IM‐1918 inhibited the phosphorylation of fibroblast growth factor receptors 1 and 3. In a bleomycin‐induced murine lung fibrosis model, IM‐1918 profoundly reduced fibrotic areas and decreased collagen and α‐smooth muscle actin accumulation. These results suggest that IM‐1918 can be applied to treat lung fibrosis. [ABSTRACT FROM AUTHOR]