ABSTRACT
BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Cholangiocarcinoma , Pyrazoles , Humans , Female , Male , Middle Aged , Aged , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Pyrazoles/therapeutic use , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Adult , Quinoxalines/therapeutic use , Quinoxalines/administration & dosage , Quinoxalines/adverse effects , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/genetics , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/genetics , Asian People , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Progression-Free Survival , Aged, 80 and overABSTRACT
Fibroblasts are cells of mesenchymal origin that are found throughout the body. While these cells have several functions, their integral roles include maintaining tissue architecture through the production of key extracellular matrix components, and participation in wound healing after injury. Fibroblasts are also key mediators in disease progression during fibrosis, cancer, and other inflammatory diseases. Under these perturbed states, fibroblasts can activate into inflammatory fibroblasts or contractile myofibroblasts. Fibroblasts require various growth factors and mitogenic molecules for survival, proliferation, and differentiation. While the activity of mitogenic growth factors on fibroblasts in vitro was characterized as early as the 1970s, the proliferation and differentiation effects of growth factors on these cells in vivo are unclear. Recent work exploring the heterogeneity of fibroblasts raises questions as to whether all fibroblast cell states exhibit the same growth factor requirements. Here, we will examine and review existing studies on the influence of fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), and transforming growth factor ß receptor (TGFßR) on fibroblast cell states.
Subject(s)
Fibroblasts , Homeostasis , Receptors, Fibroblast Growth Factor , Receptors, Platelet-Derived Growth Factor , Humans , Fibroblasts/metabolism , Receptors, Platelet-Derived Growth Factor/metabolism , Animals , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Transforming Growth Factor beta/metabolismABSTRACT
Fibroblast growth factors (FGFs) are a versatile family of peptide growth factors that are involved in various biological functions, including cell growth and differentiation, embryonic development, angiogenesis, and metabolism. Abnormal FGF/FGF receptor (FGFR) signaling has been implicated in the pathogenesis of multiple diseases such as cancer, metabolic diseases, and inflammatory diseases. It is worth noting that macrophage polarization, which involves distinct functional phenotypes, plays a crucial role in tissue repair, homeostasis maintenance, and immune responses. Recent evidence suggests that FGF/FGFR signaling closely participates in the polarization of macrophages, indicating that they could be potential targets for therapeutic manipulation of diseases associated with dysfunctional macrophages. In this article, we provide an overview of the structure, function, and downstream regulatory pathways of FGFs, as well as crosstalk between FGF signaling and macrophage polarization. Additionally, we summarize the potential application of harnessing FGF signaling to modulate macrophage polarization.
Subject(s)
Fibroblast Growth Factors , Macrophages , Receptors, Fibroblast Growth Factor , Signal Transduction , Humans , Macrophages/immunology , Macrophages/metabolism , Fibroblast Growth Factors/metabolism , Animals , Receptors, Fibroblast Growth Factor/metabolism , Macrophage Activation/immunology , Inflammation/immunology , Inflammation/metabolismABSTRACT
Fibroblast growth factors (FGFs) act as proangiogenic and mitogenic cytokines in several cancers, including multiple myeloma (MM). Indeed, corrupted FGF autocrine and paracrine secretion induces an aberrant activation of the FGF receptor (FGFR) signaling sustaining cancer cell spreading and resistance to pharmacological treatments. Thus, FGF traps may represent a promising anti-cancer strategy to hamper the ligand-dependent activation of the FGF/FGFR system. We previously identified NSC12 as the first orally available small molecule FGF trap able to inhibit the growth and progression of several FGF-dependent tumor models. NSC12 is a pregnenolone derivative carrying a 1,1-bis-trifluoromethyl-1,3-propanediol chain in position 17 of the steroid nucleus. Investigation of structure-activity relationships (SARs) provided more potent and specific NSC12 steroid derivatives and highlighted that the C17-side chain is pivotal for the FGF trap activity. Here, a scaffold hopping approach allowed to obtain two FGF trap compounds (22 and 57) devoid of the steroid nucleus and able to efficiently bind FGF2 and to inhibit FGFR activation in MM cells. Accordingly, these compounds exert a potent anti-tumor activity on MM cell lines both in vitro and in vivo and on MM patient-derived primary cells, strongly affecting the survival of both proteasome-inhibitor sensitive and resistant MM cells. These results propose a new therapeutic option for relapsed/refractory MM patients and set the bases for the development of novel FGF traps prone to chemical diversification to be used in the clinic for the treatment of those tumors in which the FGF/FGFR system plays a pivotal role, including MM.
Subject(s)
Antineoplastic Agents , Fibroblast Growth Factors , Multiple Myeloma , Receptors, Fibroblast Growth Factor , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Humans , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Cell Line, Tumor , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/metabolism , Fibroblast Growth Factors/metabolism , Structure-Activity Relationship , Drug Discovery , Mice , Fibroblast Growth Factor 2/metabolismABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Neoplasms , Pyrimidines , Humans , Male , Female , Middle Aged , Aged , Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Adult , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Immunotherapy/methods , Molecular Targeted Therapy , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Morpholines , PyrrolesABSTRACT
The FGF system is the most complex of all receptor tyrosine kinase signaling networks with 18 FGF ligands and four FGFRs that deliver morphogenic signals to pattern most embryonic structures. Even when a single FGFR is expressed in the tissue, different FGFs can trigger dramatically different biological responses via this receptor. Here we show both quantitative and qualitative differences in the signaling of one of the FGF receptors, FGFR1c, in response to different FGFs. We provide an overview of the recent discovery that FGFs engage in biased signaling via FGFR1c. We discuss the concept of ligand bias, which represents qualitative differences in signaling as it is a measure of differential ligand preferences for different downstream responses. We show how FGF ligand bias manifests in functional data in cultured chondrocyte cells. We argue that FGF-ligand bias contributes substantially to FGF-driven developmental processes, along with known differences in FGF expression levels, FGF-FGFR binding coefficients and differences in FGF stability in vivo.
Subject(s)
Fibroblast Growth Factors , Receptor, Fibroblast Growth Factor, Type 1 , Receptors, Fibroblast Growth Factor , Signal Transduction , Fibroblast Growth Factors/metabolism , Animals , Humans , Ligands , Receptors, Fibroblast Growth Factor/metabolism , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Chondrocytes/metabolismABSTRACT
AIM: Neuroblastoma (NB) is, in spite of current intensive therapy with severe side effects, still not cured so new therapies are needed. Recently, we showed combining phosphoinositide 3-kinase (PI3K) (BYL719), fibroblast growth factor receptor (FGFR) (JNJ-42756493) and cyclin-dependent kinase 4/6 (CDK4/6) (PD-0332991) inhibitors, in vitro in NB cell lines grown as monolayers had synergistic effects. However, there were variations depending on the combinations used and the targeted NB cell lines. To obtain further information and to mimic more natural circumstances, we investigated the effects of single and combined administrations of the above inhibitors in spheroid NB-cultures. MATERIAL AND METHODS: Spheroid cultures of NB cell lines SK-N-AS, SK-N-BE(2)-C, SK-N-FI and SK-N-SH were established and treated with single and combined administrations of BYL719, JNJ-42756493, and PD-0332991 and followed for growth, viability, proliferation, cytotoxicity and migration. KEY FINDINGS: Single inhibitor administrations gave dose dependent responses with regard to growth and viability and their combinations were efficient and resulted in a range of additive and synergistic effects. The responses to individual drugs and their various combinations were predominantly alike regardless of whether the cells were cultivated in monolayer or D spheroid NB models. However, in general, slightly higher drug concentrations were necessary in spheroidcultures. SIGNIFICANCE: This study provides pre-clinical evidence that single PI3K, FGFR, and CDK4/6, inhibitors exhibit promising anti-NB activity and when combined lower doses of the drugs could be also used in spheroid NB-cultures, supporting the pursuit of further in vitro and in vivo studies in preparation for future potential clinical use.
Subject(s)
Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Drug Synergism , Neuroblastoma , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors , Receptors, Fibroblast Growth Factor , Spheroids, Cellular , Neuroblastoma/drug therapy , Neuroblastoma/pathology , Humans , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Spheroids, Cellular/drug effects , Cell Line, Tumor , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/metabolism , Protein Kinase Inhibitors/pharmacology , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , Cell Proliferation/drug effects , Pyridines/pharmacology , Molecular Targeted Therapy , Phosphatidylinositol 3-Kinases/metabolism , Cell Survival/drug effects , Piperazines/pharmacology , Piperazines/administration & dosage , Dose-Response Relationship, DrugABSTRACT
The number of adults living with cystic fibrosis (CF) has already increased significantly because of drastic improvements in life expectancy attributable to advances in treatment, including the development of highly effective modulator therapy. Chronic airway inflammation in CF contributes to morbidity and mortality, and aging processes like inflammaging and cell senescence influence CF pathology. Our results show that single-cell RNA sequencing data, human primary bronchial epithelial cells from non-CF and CF donors, a CF bronchial epithelial cell line, and Cftr-knockout (Cftr-/-) rats all demonstrated increased cell senescence markers in the CF bronchial epithelium. This was associated with upregulation of fibroblast growth factor receptors (FGFRs) and mitogen-activated protein kinase (MAPK) p38. Inhibition of FGFRs, specifically FGFR4 and to some extent FGFR1, attenuated cell senescence and improved mucociliary clearance, which was associated with MAPK p38 signaling. Mucociliary dysfunction could also be improved using a combination of senolytics in a CF ex vivo model. In summary, FGFR/MAPK p38 signaling contributes to cell senescence in CF airways, which is associated with impaired mucociliary clearance. Therefore, attenuation of cell senescence in the CF airways might be a future therapeutic strategy improving mucociliary dysfunction and lung disease in an aging population with CF.
Subject(s)
Cellular Senescence , Cystic Fibrosis , Respiratory Mucosa , Cystic Fibrosis/metabolism , Cystic Fibrosis/pathology , Cystic Fibrosis/genetics , Cystic Fibrosis/drug therapy , Humans , Animals , Rats , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Fibroblast Growth Factor/genetics , Epithelial Cells/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Male , Disease Models, Animal , Cell Line , Bronchi/pathology , Bronchi/metabolism , Signal Transduction , FemaleABSTRACT
Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.
Subject(s)
Cell Differentiation , Fibroblast Growth Factors , Receptors, Fibroblast Growth Factor , Signal Transduction , Animals , Humans , Receptors, Fibroblast Growth Factor/metabolism , Fibroblast Growth Factors/metabolism , Mice , Ligands , Calcium/metabolism , MAP Kinase Signaling SystemABSTRACT
The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC50 = 46, 41, 99, and 62 nM). Moreover, 10h also strongly suppressed the proliferation of NCI-H520 lung cancer cells, SNU-16 and KATO III gastric cancer cells with IC50 values of 19, 59, and 73 nM, respectively. Further X-ray co-crystal structure revealed that 10h irreversibly binds to FGFR1. The study provides a new promising point for anticancer drug development medicated by FGFRs.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Drug Design , Pyrazoles , Receptors, Fibroblast Growth Factor , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Models, Molecular , Molecular Structure , Pyrazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/metabolism , Structure-Activity Relationship , /chemistry , /pharmacologyABSTRACT
The FGFR signaling pathway is integral to cellular activities, including proliferation, differentiation, and survival. Dysregulation of this pathway is implicated in numerous human cancers, positioning FGFR as a prominent therapeutic target. Here, we conduct a comprehensive review of the function, signaling pathways and abnormal alterations of FGFR, as well as its role in tumorigenesis and development. Additionally, we provide an in-depth analysis of pivotal phase 2 and 3 clinical trials evaluating the performance and safety of FGFR inhibitors in oncology, thereby shedding light on the current state of clinical research in this field. Then, we highlight four drugs that have been approved for marketing by the FDA, offering insights into their molecular mechanisms and clinical achievements. Our discussion encompasses the intricate landscape of FGFR-driven tumorigenesis, current techniques for pinpointing FGFR anomalies, and clinical experiences with FGFR inhibitor regimens. Furthermore, we discuss the inherent challenges of targeting the FGFR pathway, encompassing resistance mechanisms such as activation by gatekeeper mutations, alternative pathways, and potential adverse reactions. By synthesizing the current evidence, we underscore the potential of FGFR-centric therapies to enhance patient prognosis, while emphasizing the imperative need for continued research to surmount resistance and optimize treatment modalities.
Subject(s)
Neoplasms , Receptors, Fibroblast Growth Factor , Signal Transduction , Humans , Neoplasms/drug therapy , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Signal Transduction/drug effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Molecular Targeted Therapy/methods , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , AnimalsABSTRACT
Fibroblast Growth Factor Receptor (FGFR) is connected to numerous downstream signalling cascades regulating cellular behavior. Any dysregulation leads to a plethora of illnesses, including cancer. Therapeutics are available, but drug resistance driven by gatekeeper mutation impedes the treatment. Ponatinib is an FDA-approved drug against BCR-ABL kinase and has shown effective results against FGFR-mediated carcinogenesis. Herein, we undertake molecular dynamics simulation-based analysis on ponatinib against all the FGFR isoforms having Val to Met gatekeeper mutations. The results suggest that ponatinib is a potent and selective inhibitor for FGFR1, FGFR2, and FGFR4 gatekeeper mutations. The extensive electrostatic and van der Waals interaction network accounts for its high potency. The FGFR3_VM mutation has shown resistance towards ponatinib, which is supported by their lesser binding affinity than wild-type complexes. The disengaged molecular brake and engaged hydrophobic spine were believed to be the driving factors for weak protein-ligand interaction. Taken together, the inhibitory and structural characteristics exhibited by ponatinib may aid in thwarting resistance based on Val-to-Met gatekeeper mutations at an earlier stage of treatment and advance the design and development of other inhibitors targeted at FGFRs harboring gatekeeper mutations.
Subject(s)
Imidazoles , Molecular Dynamics Simulation , Mutation , Protein Binding , Pyridazines , Pyridazines/chemistry , Pyridazines/pharmacology , Pyridazines/metabolism , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazoles/metabolism , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Fibroblast Growth Factor/chemistry , Receptors, Fibroblast Growth Factor/geneticsABSTRACT
Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Neoplasms , Pyrazoles , Humans , Male , Female , Middle Aged , Aged , Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/therapeutic use , Adult , Quinoxalines/adverse effects , Quinoxalines/administration & dosage , Quinoxalines/therapeutic use , Quinoxalines/pharmacokinetics , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacokinetics , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Maximum Tolerated Dose , Dose-Response Relationship, Drug , Japan , Aged, 80 and over , East Asian PeopleABSTRACT
Erdafitinib, a selective and potent oral pan-FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open-label, single-sequence, drug-drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co-administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co-administration decreased total and free maximum plasma concentrations of erdafitinib (Cmax) by 35% (95% CI 30%-39%) and 22% (95% CI 17%-27%), respectively. The areas under the concentration-time curve over the time interval from 0 to 168 hours, to the last quantifiable data point, and to time infinity (AUC168h, AUClast, AUCinf), were markedly decreased for both total erdafitinib (56%-62%) and free erdafitinib (48%-55%). The safety profile of erdafitinib was consistent with previous clinical studies in healthy participants, with no new safety concerns when administered with or without carbamazepine. Co-administration with carbamazepine may reduce the activity of erdafitinib due to reduced exposure. Concomitant use of strong CYP3A4 inducers with erdafitinib should be avoided.
Subject(s)
Area Under Curve , Carbamazepine , Cytochrome P-450 CYP3A , Drug Interactions , Healthy Volunteers , Humans , Adult , Male , Female , Carbamazepine/pharmacology , Carbamazepine/pharmacokinetics , Carbamazepine/administration & dosage , Young Adult , Cytochrome P-450 CYP3A/metabolism , Middle Aged , Cytochrome P-450 CYP3A Inducers/pharmacology , Cytochrome P-450 CYP2C9/metabolism , Pyrazoles/pharmacokinetics , Pyrazoles/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/pharmacology , Quinoxalines/pharmacokinetics , Quinoxalines/adverse effects , Quinoxalines/administration & dosage , Quinoxalines/pharmacology , Administration, Oral , Receptors, Fibroblast Growth Factor/antagonists & inhibitorsABSTRACT
Immune checkpoint inhibitors (ICIs) are essential for urothelial carcinoma (UC) treatment. Fibroblast growth factor receptor (FGFR) alterations, as common oncogenic drivers in UC, have been reported to drive T cell depletion of UC immune microenvironment via up-regulating FGFR signaling, which indicated FGFR alterations potentially result in reduced response to ICIs. In addition, the selective pan-FGFR inhibitor showed better clinical benefit in clinical trials, indicating FGFR has emerged as critical therapeutic target via inhibiting FGFR signaling. The present study aims to evaluate prognosis and response to ICIs between FGFR-altered UC patients and FGFR-wildtype UC patients via 1963 UC patients and offers new insights into personalized precision therapy and combination therapy for UC.
Subject(s)
Immune Checkpoint Inhibitors , Receptors, Fibroblast Growth Factor , Humans , Immune Checkpoint Inhibitors/therapeutic use , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Immunotherapy/methods , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/immunology , Urologic Neoplasms/drug therapy , Urologic Neoplasms/immunology , Prognosis , Female , Male , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/immunologyABSTRACT
Fibroblast growth factors (FGFs) and their receptors (FGFRs) constitute plasma-membrane localized signaling hubs that transmit signals from the extracellular environment to the cell interior, governing pivotal cellular processes like motility, metabolism, differentiation, division and death. FGF/FGFR signaling is critical for human body development and homeostasis; dysregulation of FGF/FGFR units is observed in numerous developmental diseases and in about 10% of human cancers. Glycosylation is a highly abundant posttranslational modification that is critical for physiological and pathological functions of the cell. Glycosylation is also very common within FGF/FGFR signaling hubs. Vast majority of FGFs (15 out of 22 members) are N-glycosylated and few FGFs are O-glycosylated. Glycosylation is even more abundant within FGFRs; all FGFRs are heavily N-glycosylated in numerous positions within their extracellular domains. A growing number of studies points on the multiple roles of glycosylation in fine-tuning FGF/FGFR signaling. Glycosylation modifies secretion of FGFs, determines their stability and affects interaction with FGFRs and co-receptors. Glycosylation of FGFRs determines their intracellular sorting, constitutes autoinhibitory mechanism within FGFRs and adjusts FGF and co-receptor recognition. Sugar chains attached to FGFs and FGFRs constitute also a form of code that is differentially decrypted by extracellular lectins, galectins, which transform FGF/FGFR signaling at multiple levels. This review focuses on the identified functions of glycosylation within FGFs and FGFRs and discusses their relevance for the cell physiology in health and disease.
Subject(s)
Fibroblast Growth Factors , Receptors, Fibroblast Growth Factor , Signal Transduction , Humans , Glycosylation , Fibroblast Growth Factors/metabolism , Receptors, Fibroblast Growth Factor/metabolism , Animals , Protein Processing, Post-TranslationalABSTRACT
Anti-FGFR treatment for cholangiocarcinoma (CCA) with fibroblast growth factor receptor (FGFR) alteration is a promising treatment option. Since the antitumor mechanisms of anti-FGFR inhibitors and conventional cytotoxic drugs differ, synergistic effects can be possible. This study aimed to evaluate the efficacy of the combined administration of gemcitabine (GEM) and pemigatinib in CCA cells with FGFR2 alterations. To simulate the treatment for patients with 3 kinds of CCA, chemonaïve CCA with activation of the FGF pathway, chemo-resistant CCA with activation of the FGF pathway, and CCA without FGF pathway activation (as controls), we evaluated 3 different CCA cell lines, CCLP-1 (with a FGFR2 fusion mutation), CCLP-GR (GEM-resistant cells established from CCLP-1), and HuCCT1 (without FGFR mutations). There was no significant difference between CCLP-1 and HuCCT1 in GEM suspensibility (IC50 = 19.3, 22.6 mg/dl, p = 0.1187), and the drug sensitivity to pemigatinib did not differ between CCLP-1 and CCLP-GR (IC50 = 7.18,7.60 nM, p = 0.3089). Interestingly, only CCLP-1 showed a synergistic effect with combination therapy consisting of GEM plus pemigatinib in vitro and in vivo. In a comparison of the reaction to GEM exposure, only CCLP-1 cells showed an increase in the activation of downstream proteins in the FGF pathway, especially FRS2 and ERK. In association with this reaction, cell cycle and mitosis were increased with GEM exposure in CCLP-1, but HuCCT1/CCLP-GR did not show this reaction. Our results suggested that combination therapy with GEM plus pemigatinib is a promising treatment for chemonaïve patients with CCA with activation of the FGF pathway.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bile Duct Neoplasms , Cholangiocarcinoma , Deoxycytidine , Drug Synergism , Gemcitabine , Pyrimidines , Receptor, Fibroblast Growth Factor, Type 2 , Xenograft Model Antitumor Assays , Humans , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/genetics , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/administration & dosage , Animals , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/genetics , Cell Line, Tumor , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Pyrimidines/pharmacology , Pyrimidines/administration & dosage , Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Receptor, Fibroblast Growth Factor, Type 2/genetics , Mice , Cell Proliferation/drug effects , Mice, Nude , Signal Transduction/drug effects , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/genetics , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/metabolism , Drug Resistance, Neoplasm/drug effects , Protein Kinase Inhibitors/pharmacology , Mutation , Apoptosis/drug effects , Morpholines , PyrrolesABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which therapeutic options are limited, with an unmet need to identify new therapeutic targets. IPF is thought to be the consequence of repeated microlesions of the alveolar epithelium, leading to aberrant epithelial-mesenchymal communication and the accumulation of extracellular matrix proteins. The reactivation of developmental pathways, such as Fibroblast Growth Factors (FGFs), is a well-described mechanism during lung fibrogenesis. Secreted FGFs with local paracrine effects can either exert an anti-fibrotic or a pro-fibrotic action during this pathological process through their FGF receptors (FGFRs) and heparan sulfate residues as co-receptors. Among FGFs, endocrine FGFs (FGF29, FGF21, and FGF23) play a central role in the control of metabolism and tissue homeostasis. They are characterized by a low affinity for heparan sulfate, present in the cell vicinity, allowing them to have endocrine activity. Nevertheless, their interaction with FGFRs requires the presence of mandatory co-receptors, alpha and beta Klotho proteins (KLA and KLB). Endocrine FGFs are of growing interest for their anti-fibrotic action during liver, kidney, or myocardial fibrosis. Innovative therapies based on FGF19 or FGF21 analogs are currently being studied in humans during liver fibrosis. Recent data report a similar anti-fibrotic action of endocrine FGFs in the lung, suggesting a systemic regulation of the pulmonary fibrotic process. In this review, we summarize the current knowledge on the protective effect of endocrine FGFs during the fibrotic processes, with a focus on pulmonary fibrosis.
Subject(s)
Fibroblast Growth Factors , Pulmonary Fibrosis , Animals , Humans , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/metabolism , Receptors, Fibroblast Growth Factor/metabolism , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathologyABSTRACT
We performed a comparative in vitro study of the involvement of NF-κB, PI3K, cAMP, ERK1/2, p38, JAKs, STAT3, JNK, and p53-dependent intracellular signaling in the functioning of neural stem cells (NSC) under the influence of basic fibroblast growth factor (FGF) and FGF receptor agonist, diterpene alkaloid songorine. The significant differences in FGFR-mediated intracellular signaling in NSC were revealed for these ligands. In both cases, stimulation of progenitor cell proliferation occurs with the participation of NF-κB, PI3K, ERK1/2, JAKs, and STAT3, while JNK and p53, on the contrary, inhibit cell cycle progression. However, under the influence of songorin, cAMP- and p38-mediated cascades are additionally involved in the transmission of the NSC division-activating signal. In addition, unlike FGF, the alkaloid stimulates progenitor cell differentiation by activating ERK1/2, p38, JNK, p53, and STAT3.
Subject(s)
Cell Differentiation , Cell Proliferation , Diterpenes , Neural Stem Cells , Receptors, Fibroblast Growth Factor , STAT3 Transcription Factor , Signal Transduction , Neural Stem Cells/drug effects , Neural Stem Cells/metabolism , Neural Stem Cells/cytology , Animals , STAT3 Transcription Factor/metabolism , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Fibroblast Growth Factor/agonists , Signal Transduction/drug effects , Cell Proliferation/drug effects , Diterpenes/pharmacology , Cell Differentiation/drug effects , NF-kappa B/metabolism , Fibroblast Growth Factor 2/metabolism , Fibroblast Growth Factor 2/pharmacology , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/agonists , Phosphatidylinositol 3-Kinases/metabolism , Alkaloids/pharmacology , MAP Kinase Signaling System/drug effects , Janus Kinases/metabolism , Cyclic AMP/metabolism , Cells, Cultured , RatsABSTRACT
This review article explores the intricate correlation between growth factors and bone metastases, which play a crucial role in the development of several types of malignancies, namely breast, prostate, lung, and renal cancers. The focal point of our discussion is on crucial receptors for growth factors, including Epidermal Growth Factor Receptor (EGFR), Transforming Growth Factor-ß (TGFß), Vascular Endothelial Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR). These receptors, which are essential for cellular activities including growth, differentiation, and survival, have important involvement in the spread of cancer and the interactions between tumors and the bone environment. We discuss the underlying mechanisms of bone metastases, with a specific emphasis on the interaction between growth factor receptors and the bone microenvironment. EGFR signaling specifically enhances the process of osteoclast development and the formation of osteolytic lesions, especially in breast and lung malignancies. TGFß receptors have a role in both osteolytic and osteoblastic metastases by releasing TGFß, which attracts cancer cells and promotes bone remodeling. This is a crucial element in the spread of prostate cancer to the bones. The functions of FGFR and VEGFR in the processes of bone formation and tumor angiogenesis, respectively, highlight the complex and diverse nature of these interactions. The review emphasizes the possibility of targeted therapeutics targeting these receptors to interrupt the cycle of tumor development and bone degradation. Therapeutic approaches include focusing on the VEGF/VEGFR, EGF/EGFR, FGF/FGFR, and TGFß/TGFßR pathways. These include a variety of compounds, such as small molecule inhibitors and monoclonal antibodies, which have shown potential to interfere with tumor-induced alterations in bone. The text discusses clinical trials and preclinical models, offering insights into the effectiveness and constraints of various treatments. Ultimately, this study provides a succinct but thorough summary of the present knowledge and treatment strategies focused on growth factor receptors in bone metastases. This highlights the significance of comprehending the signaling of growth factor receptors in the microenvironment where tumors spread to the bones, as well as the possibility of using targeted therapies to enhance the results for cancer patients with bone metastases. The advancement of treating bone metastases hinges on the development of treatments that specifically target the intricate relationships between malignancies and bone.