Anti-fibroblast Growth Factor Receptor Research Articles

How Immunotherapy Has Redefined the Treatment Paradigm of Metastatic or Locally Advanced Muscle-Invasive Urothelial Bladder Carcinoma.

In the past decade, the therapeutic arsenal for metastatic bladder cancer has expanded considerably, with the development of immune checkpoint inhibitors (ICIs), antibody-drug conjugates such as enfortumab vedotin, and anti-fibroblast growth factor receptor agents. Clinical trials evaluating ICIs as neoadjuvants, adjuvants, or first- or second-line treatments have produced conflicting results. However, first-line therapeutic strategies have been redefined by the recent publication of results from two clinical trials: CheckMate-901, which demonstrated the superiority of combined treatment with nivolumab and chemotherapy in extending overall survival, and EV-302, which demonstrated that combined treatment with pembrolizumab and enfortumab vedotin reduced the risk of death by 53%. In this review, we discuss the role of ICIs, alone or in combination, in bladder cancer management in the metastatic and adjuvant settings in 2024, considering the latest published trials. The potential role of ICIs as neoadjuvants is also discussed.

Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies.

BackgroundMuscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies, or anti-fibroblast growth factor receptor (FGFR) treatments, these tumors are still of a poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) recapitulating the molecular heterogeneity of MIBC and UTUC, to facilitate the preclinical identification of therapies.MethodsFresh tumors were obtained from patients and subcutaneously engrafted into immune-compromised mice. Patient tumors and matched PDXs were compared regarding histopathology, transcriptomic (microarrays), and genomic profiles [targeted Next-Generation Sequencing (NGS)]. Several PDXs were treated with chemotherapy (cisplatin/gemcitabine) or targeted therapies [FGFR and epidermal growth factor (EGFR) inhibitors].ResultsA total of 31 PDXs were established from 1 non-MIBC, 25 MIBC, and 5 upper urinary tract tumors, including 28 urothelial (UC) and 3 squamous cell carcinomas (SCCs). Integrated genomic and transcriptomic profiling identified the PDXs of three different consensus molecular subtypes [basal/squamous (Ba/Sq), luminal papillary, and luminal unstable] and included FGFR3-mutated PDXs. High histological and genomic concordance was found between matched patient tumor/PDX. Discordance in molecular subtypes, such as a Ba/Sq patient tumor giving rise to a luminal papillary PDX, was observed (n=5) at molecular and histological levels. Ten models were treated with cisplatin-based chemotherapy, and we did not observe any association between subtypes and the response. Of the three Ba/Sq models treated with anti-EGFR therapy, two models were sensitive, and one model, of the sarcomatoid variant, was resistant. The treatment of three FGFR3-mutant PDXs with combined FGFR/EGFR inhibitors was more efficient than anti-FGFR3 treatment alone.ConclusionsWe developed preclinical PDX models that recapitulate the molecular heterogeneity of MIBCs and UTUC, including actionable mutations, which will represent an essential tool in therapy development. The pharmacological characterization of the PDXs suggested that the upper urinary tract and MIBCs, not only UC but also SCC, with similar molecular characteristics could benefit from the same treatments including anti-FGFR for FGFR3-mutated tumors and anti-EGFR for basal ones and showed a benefit for combined FGFR/EGFR inhibition in FGFR3-mutant PDXs, compared to FGFR inhibition alone.

Covariate effects and population pharmacokinetic analysis of the anti-FGFR2b antibody bemarituzumab in patients from phase 1 to phase 2 trials

PurposeA population pharmacokinetic (PK) analysis of the anti-fibroblast growth factor receptor 2b antibody, bemarituzumab, was performed to evaluate the impact of covariates on the PK and assess whether dose adjustment is necessary for a future phase 3 trial.MethodsSerum concentration data were obtained from three clinical trials, with 1552 bemarituzumab serum samples from 173 patients, and were analyzed using nonlinear mixed-effects modeling.ResultsA two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment best described the bemarituzumab serum concentration data. The final model estimated a typical linear clearance (CL) of 0.311 L/day, volume of distribution in the central compartment (Vc) of 3.58 L, distribution clearance (Q) of 0.952 L/day, volume of distribution in the peripheral compartment (Vp) of 2.71 L, maximum drug elimination by nonlinear clearance (Vmax) of 2.80 μg/day, and Michaelis–Menten constant (Km) of 4.45 μg/mL. Baseline body weight, baseline albumin, gender, and chemotherapy were identified as statistically significant covariates on the PK of bemarituzumab. Given the low interindividual variability of bemarituzumab key PK parameters (CL and Vc) and the small or modest effect of all statistically significant covariates on bemarituzumab exposure at steady-state, no covariate is expected to have clinically meaningful effects on bemarituzumab exposure.ConclusionNo covariate had a clinically meaningful impact on bemarituzumab exposure. These results indicate that dose adjustment of bemarituzumab is not necessary, based on the aforementioned covariates, for a future phase 3 trial in gastric and gastroesophageal junction adenocarcinoma population with FGFR2b overexpression in combination with mFOLFOX6.

Clinical features with anti fibroblast growth factor receptor 3 (FGFR3) antibody-related polyneuropathy: a retrospective study

BackgroundDespite its initial association with sensory neuropathies, anti-fibroblast growth factor receptor 3 (FGFR3) antibodies have been since reported with a broad range of neuropathies and clinical features. The aim of the study is to report the clinical and electro diagnostic findings in a cohort of patients with sensory or sensorimotor polyneuropathy and anti-FGFR3 antibodies.MethodsWe performed a retrospective chart review to assess the clinical characteristics of patients with sensory or sensorimotor neuropathy related to FGFR3 antibodies. Descriptive statistics were reported using frequencies and percentages for categorical variables and median and interquartile range (IQR) for continuous variables.ResultsThis study included 14 patients (9 women) with a median age of 51.9 years (IQR 48–57). The most common presenting symptoms were painful paresthesia (100%), gait instability (42.9%), constitutional symptoms (42.9%), and autonomic symptoms (28.6%). Onset of symptoms was chronic (≥12 weeks) in eight patients (57.1%). Examination showed a distal loss of sensation to pin prick (100%), as well as impaired vibration sensation (78.6%) and proprioception (35.7%), in the distal extremities. We also observed mild weakness in the distal lower-extremities (42.9%). Three patients (21.4%) had trigeminal neuralgia, three patients (21.4%) had co-existing autoimmune disease, and one patient (7.1%) had a history of renal cell carcinoma. The mean titer of FGFR3 antibody was 14,285.71 (IQR 5000–16,750). All 14 patients produced normal results in the neuropathy workup. Nerve conduction study and electromyography showed sensory axonal neuropathy in four patients (28.6%), sensorimotor axonal neuropathy in seven patients (50%), and a normal result in three patients (21.4%). For those with a normal NCS/EMG, a skin biopsy showed a non-length-dependent small fiber neuropathy.ConclusionsNeuropathy related to FGFR3 antibodies can potentially involve small and large fibers, sensory and motor fibers, and even the trigeminal nerve, which contributes to a highly variable clinical presentation.

Targetable gene fusions and aberrations in genitourinary oncology.

Gene fusions result from either structural chromosomal rearrangement or aberrations caused by splicing or transcriptional readthrough. The precise and distinctive presence of fusion genes in neoplastic tissues and their involvement in multiple pathways central to cancer development, growth and survival make them promising targets for personalized therapy. In genitourinary malignancies, rearrangements involving the E26 transformation-specific family of transcription factors have emerged as very frequent alterations in prostate cancer, especially the TMPRSS2-ERG fusion. In renal malignancies, Xp11 and t(6;11) translocations are hallmarks of a distinct pathological group of tumours described as microphthalmia-associated transcription factor family translocation-associated renal cell carcinomas. Novel druggable fusion events have been recognized in genitourinary malignancies, leading to the activation of several clinical trials. For instance, ALK-rearranged renal cell carcinomas have shown responses to alectinib and crizotinib. Erdafitinib has been tested for the treatment of FGFR-rearranged bladder cancer. Other anti-fibroblast growth factor receptor 3 (FGFR3) compounds are showing promising results in the treatment of bladder cancer, including infigratinib and pemigatinib, and all are currently in clinical trials.

Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial

PurposeTo report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab.MethodsNonlinear mixed-effect modeling was used to analyse PK data. In vitro binding affinity and receptor occupancy of bemarituzumab were determined. Simulation was conducted to estimate dose and schedule to achieve an empirical target Ctrough in a phase 2 trial (FIGHT, NCT03694522) for patients receiving first-line treatment combined with modified 5-fluourouracil, oxaliplatin and leucovorin (mFOLFOX6) for gastric and gastroesophageal junction adenocarcinoma.ResultsBemarituzumab PK is best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. Albumin, gender, and body weight were identified as the covariates on the linear clearance and/or volume of distribution in the central compartment, and no dose adjustment was warranted. An empirical target of bemarituzumab Ctrough of ≥ 60 µg/mL was projected to achieve > 95% receptor occupancy based on in vitro data. Fifteen mg/kg every 2 weeks, with a single dose of 7.5 mg/kg on Cycle 1 Day 8, was projected to achieve the target Ctrough on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial.ConclusionA projected dose and schedule to achieve the target Ctrough was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.

Sensory neuronopathy is a specific and disabling neurological manifestation of autoimmune hepatitis

Neurological manifestations have been identified in the context of autoimmune hepatitis (AIH). Previous case reports highlighted the association between AIH and sensory neuronopathy (SN). Despite that, little is known about the frequency of AIH-related SN and its clinical/neurophysiological profile. Moreover, it is not clear whether SN is an AIH-specific manifestation or related to chronic liver damage. Seventy consecutive AIH patients were enrolled and their characteristics were compared with 52 consecutive patients with chronic active hepatitis B. All subjects underwent clinical and neurophysiological evaluation. Further comparisons were performed between AIH SN and AIH non-SN patients. Mean ages and male:female proportions in the AIH and chronic active hepatitis B groups were 42.2±16.3/51.7±13.6years and 14:56/29:23, respectively. The frequencies of carpal tunnel syndrome, radiculopathy and polyneuropathy were similar between groups. In contrast, SN was identified only in AIH patients (5/70 vs. 0/52, P=0.04); the overall prevalence of AIH-related SN was 7% with an average profile of a woman in her 40s with asymmetric onset of sensory deficits that chronically evolved to disabling proprioceptive ataxia associated with marked dysautonomia. Neurological disability and hepatocellular damage did not follow in parallel. Anti-fibroblast growth factor receptor type 3 antibodies were found in 3/5 (60%) of the patients with AIH-related SN. Clinical or demographic predictors of SN in the context of AIH could not be identified. Sensory neuronopathy, but not other peripheral nervous system diseases, is a specific AIH neurological manifestation. It is often disabling and, in contrast to hepatocellular injury, does not respond to immunosuppression.

Effect of anti-fibroblast growth factor receptor 1 antibodies on phosphorus metabolism in laying hens and their progeny chicks

Targeting fibroblast growth factor 23 (FGF-23) signaling pathway is of interest in controlling body phosphate metabolism. This study investigated the effect of anti-fibroblast growth factor receptor 1 (FGFR1, major FGF-23 receptor in the kidney) antibodies on phosphate metabolism. White Leghorn laying hens (65-wk-old) were vaccinated with either a FGFR1 peptide vaccine (five 8-amino-acid peptides were selected, CrZ-1:LPEDPRWE, CrZ-2:LDKDKPNR, CrZ-3:RRPPGMEY, CrZ-4:GSPYPGVP, and CrZ-5:RMDKPSNC) or adjuvant control. At peak antibody titer, hens were artificially inseminated. Chicks from control-vaccinated hens were fed either a non-phytate phosphorus (nPP) sufficient (nPP = 0.45%, positive control) or deficient (nPP = 0.20%, negative control) diet, while chicks from each of the FGFR1 peptide vaccinated hens were fed with the above nPP-deficient diet, for 14 D. When compared to control hens, plasma phosphate in CrZ-1, CrZ-2, CrZ-3, CrZ-4, and CrZ-5 vaccinated hens were decreased by 33, 30, 24, 20, and 26%, respectively (P < 0.05); egg weight in CrZ-2 and CrZ-5 vaccinated hens were increased by 6 and 7%, respectively (P < 0.05); egg production in CrZ-3, CrZ-4, and CrZ-5 vaccinated hens tended to decrease (P= 0.085; decreased by 14, 15, and 13%, respectively). When compared to positive control, chicks from all other groups had decreased body weight gain (BWG) and feed intake (FI) during 1 to 14 D, and had decreased plasma phosphate, tibiotarsus ash, and 24-h phosphorus excretion on day 14. When compared to negative control, BWG of CrZ-1, CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 23, 28, 26, and 20%, respectively (P < 0.05); FI of CrZ-1, CrZ-2, and CrZ-3 antibody chicks were decreased by 15, 15, and 18%, respectively (P < 0.05); plasma phosphate of CrZ-5 antibody chicks were decreased by 26% (P < 0.05); plasma FGF-23 levels of CrZ-4 antibody chicks were increased by 18% (P < 0.05); tibiotarsus ash content of CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 20, 20, and 21%, respectively (P < 0.05). In conclusion, anti-FGFR1 peptide antibodies decreased egg production of hens and growth performance of their progeny chicks probably by activating FGF-23 signaling and stimulating FGF-23 production.

Reducing the risk of misdiagnosis of indirect ELISA by normalizing serum-specific background noise: The example of detecting anti-FGFR3 autoantibodies

Indirect enzyme-linked immunosorbent assay (ELISA) is an important diagnostic method as it enables the quantification of the presence of autoantibodies in human blood sera. However, unspecific binding of antibodies to the solid phase causes considerable serum-specific background noise (SSBN), involving the risk of false positive diagnosis. Therefore, we present a simple and concise, yet obvious proof-of-principle of a recently suggested normalization method. The method is based on subtracting SSBN by using non-coated ELISA wells as a control for each serum-of-interest. We performed ELISA to quantify anti-fibroblast growth factor receptor 3 (FGFR3) antibody levels in three positive controls (two anti-FGFR3-positive patients and a rabbit antiserum against FGFR3) and 58 negative controls (healthy blood donors). In all subjects, we found considerable unspecific reactivity which strongly varied among subjects. The conventional normalization method was not able to balance this strong SSBN, as demonstrated by 2/58 false positive healthy controls and one FGFR3-positive patient that was hidden in the noise (false negative). SSBN normalization reduced the frequency of false-positives to 0/58. Further, all three anti-FGFR3-positive sera were successfully detected and even doubled their z-score used to determine positivity. Albeit occupying more space on the ELISA plate, we strongly recommend considering this normalization method when working with blood sera. To better put the idea across to the community, we depict the SSBN issue and its solution in a graphic scheme. We conclude that SSBN normalization increases the sensitivity and specificity of indirect ELISA and thereby reduces the risk of false positive and false negative diagnosis. © 2019. Licensed under the Creative Commons [CC BY-NC 4.0 licence, https://doi.org/10.1016/j.jim.2019.01.004].

Rational generation of anti-fibroblast growth factor receptor 2 antibody for gastric cancer therapy

Rational generation of anti-fibroblast growth factor receptor 2 antibody for gastric cancer therapy

A pharmacology guided approach for setting limits on product-related impurities for bispecific antibody manufacturing

Introduction: bFKB1 is a humanized bispecific IgG1 antibody, created by conjoining an anti-Fibroblast Growth Factor Receptor 1 (FGFR1) half-antibody to an anti-Klothoβ (KLB) half-antibody, using the knobs-into-holes strategy. bFKB1 acts as a highly selective agonist for the FGFR1/KLB receptor complex and is intended to ameliorate obesity-associated metabolic defects by mimicking the activity of the hormone FGF21. An important aspect of the biologics product manufacturing process is to establish meaningful product specifications regarding the tolerable levels of impurities that copurify with the drug product. The aim of the current study was to determine acceptable levels of product-related impurities for bFKB1.Methods: To determine the tolerable levels of these impurities, we dosed obese mice with bFKB1 enriched with various levels of either HMW impurities or anti-FGFR1-related impurities, and measured biomarkers for KLB-independent FGFR1 signaling.Results: Here, we show that product-related impurities of bFKB1, in particular, high molecular weight (HMW) impurities and anti-FGFR1-related impurities, when purposefully enriched, stimulate FGFR1 in a KLB-independent manner. By taking this approach, the tolerable levels of product-related impurities were successfully determined.Discussion: Our study demonstrates a general pharmacology-guided approach to setting a product specification for a bispecific antibody whose homomultimer-related impurities could lead to undesired biological effects.

Clinical and Electrodiagnostic Findings in Neuropathy with Anti-Fibroblast Growth Factor Receptor 3 Antibodies (P1.455)

Clinical and Electrodiagnostic Findings in Neuropathy with Anti-Fibroblast Growth Factor Receptor 3 Antibodies (P1.455)

Fully-automated, high-throughput micro-computed tomography analysis of body composition enables therapeutic efficacy monitoring in preclinical models.

The ability to non-invasively measure body composition in mouse models of obesity and obesity-related disorders is essential for elucidating mechanisms of metabolic regulation and monitoring the effects of novel treatments. These studies aimed to develop a fully automated, high-throughput micro-computed tomography (micro-CT)-based image analysis technique for longitudinal quantitation of adipose, non-adipose and lean tissue as well as bone and demonstrate utility for assessing the effects of two distinct treatments. An initial validation study was performed in diet-induced obesity (DIO) and control mice on a vivaCT 75 micro-CT system. Subsequently, four groups of DIO mice were imaged pre- and post-treatment with an experimental agonistic antibody specific for anti-fibroblast growth factor receptor 1 (anti-FGFR1, R1MAb1), control immunoglobulin G antibody, a known anorectic antiobesity drug (rimonabant, SR141716), or solvent control. The body composition analysis technique was then ported to a faster micro-CT system (CT120) to markedly increase throughput as well as to evaluate the use of micro-CT image intensity for hepatic lipid content in DIO and control mice. Ex vivo chemical analysis and colorimetric analysis of the liver triglycerides were performed as the standard metrics for correlation with body composition and hepatic lipid status, respectively. Micro-CT-based body composition measures correlate with ex vivo chemical analysis metrics and enable distinction between DIO and control mice. R1MAb1 and rimonabant have differing effects on body composition as assessed by micro-CT. High-throughput body composition imaging is possible using a modified CT120 system. Micro-CT also provides a non-invasive assessment of hepatic lipid content. This work describes, validates and demonstrates utility of a fully automated image analysis technique to quantify in vivo micro-CT-derived measures of adipose, non-adipose and lean tissue, as well as bone. These body composition metrics highly correlate with standard ex vivo chemical analysis and enable longitudinal evaluation of body composition and therapeutic efficacy monitoring.

Antifibroblast growth factor receptor 3 antibodies identify a subgroup of patients with sensory neuropathy

BackgroundImmunological mechanisms are suspected in sensory neuropathy (SN) occurring with systemic autoimmune diseases and in some idiopathic cases, but so far there are no antibodies (Abs) identifying these neuropathies.MethodsIn the...

Abstract DDT02-01: In vitro and in vivo characterization of a novel anti-fibroblast growth factor receptor (FGFR) 2 antibody (BAY 1179470) for the treatment of gastric cancer

Abstract Gastric cancer is the second most common cause of cancer-related mortality worldwide, thus new treatment options are urgently needed. In a subset of gastric cancers, over-expression of fibroblast growth factor receptor 2 (FGFR2), a receptor tyrosine kinase, has been described and may represent a potential therapeutic target for the treatment of FGFR2-positive gastric cancer patients. To this end, we have generated a fully human anti-FGFR2 antibody (BAY 1179470) using the BioInvent Phage Display library. BAY 1179470 binds to a unique FGFR2-specific epitope that is present in all FGFR2 isoforms. Upon binding to FGFR2, BAY 1179470 induces receptor dimerization, internalization and degradation, resulting in significant tumor growth inhibition in vivo in cell line-based and patient-derived gastric cancer models overexpressing FGFR2. Additive anti-tumor efficacy in vivo was achieved by combining BAY 1179470 with either cisplatin or paclitaxel. BAY 1179470 is fully cross-reactive with FGFR2 orthologues of mouse, rat, pig, cynomolgus monkey and rhesus macaque. No significant safety findings have been seen in animal studies. Thus, BAY 1179470 represents a novel anti-FGFR2 antibody with high anti-tumor activity in gastric cancer models and an excellent preclinical safety profile. BAY 1179470 is currently being tested in a first-in-man study in all-comers (NCT01881217) in Japan. Citation Format: Charlotte Kopitz, Anette Sommer, Stefanie Hammer, Axel Harrenga, Beatrix Stelte-Ludwig, Frank Dittmer, Frank Reetz, Ekkehard May, Ruprecht Zierz, Sabine Wittemer-Rump, Christoph Schatz, H. T. Huynh, Karl Ziegelbauer, Bertolt Kreft. In vitro and in vivo characterization of a novel anti-fibroblast growth factor receptor (FGFR) 2 antibody (BAY 1179470) for the treatment of gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT02-01. doi:10.1158/1538-7445.AM2014-DDT02-01

Abstract 672: Pharmacokinetic and pharmacodynamic (PK/PD) modeling of preclinical data of a novel anti-fibroblast growth factor receptor 2(FGFR2) antibody (BAY 1179470) to guide dosing in Phase 1

Abstract BAY 1179470 is a human immunoglobulin (IgG) antibody directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed on cancer cells during tumorigenesis and metastasis. Anti-tumor efficacy of BAY 1179470 has been demonstrated in FGFR2-expressing gastric cancer mouse and rat xenograft models. No toxicologically relevant findings were observed in the repeated dose preclinical safety studies in rats and monkeys. Therefore, toxicity was not an appropriate endpoint for the first-in-man (FIM) study and dose selection was decided to be based on PK/PD modeling and predictions from preclinical efficacy data. All preclinical PK and tumor response data from mouse models were used to create a model framework to describe the PK and PK/PD as functions of BAY 1179470 dose, regimen and time. In a subsequent confirmatory step the PK/PD model derived from mouse efficacy data was applied to predict the efficacy in rats. Human PK parameters based on scaling from monkey were used to predict PK profiles in humans for a range of doses and schedules. These sets of predicted exposure were combined with the PK/PD model developed from mouse models to assess the expected efficacy for a range of human tumor doubling rates. Minimal effective doses, maximum effect and maximum effect doses, and maximal effective doses in humans were derived for various dosing intervals (1 day to 6 weeks). From the maximum effect dose the target AUC in humans was calculated and doses for the FIM study selected accordingly. The FIM study is currently ongoing in Japan (NCT01881217). Citation Format: Sabine Wittemer-Rump, Charlotte Kopitz, Hung Huynh, Lars Lindbom, Bernhard Beckermann, Motonobu Osada, Dirk Laurent, Jörg Lippert. Pharmacokinetic and pharmacodynamic (PK/PD) modeling of preclinical data of a novel anti-fibroblast growth factor receptor 2(FGFR2) antibody (BAY 1179470) to guide dosing in Phase 1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 672. doi:10.1158/1538-7445.AM2014-672

412 Pathological validation of adjuvant anti-fibroblast growth factor receptor 3 (FGFR3) treatment for bladder cancer

412 Pathological validation of adjuvant anti-fibroblast growth factor receptor 3 (FGFR3) treatment for bladder cancer

Fibroblast growth factor receptor 1 amplification is a common event in squamous cell carcinoma of the head and neck

Recently, we characterized fibroblast growth factor receptor 1 amplification as a target for a rational therapy in lung squamous cell carcinoma. Patients harboring this genetic event are currently eligible for treatment with antifibroblast growth factor receptor small-molecule inhibitors in phase I clinical trials. This has the potential to significantly improve standard therapy for lung squamous cell carcinoma patients. The aim of this study was to elucidate whether fibroblast growth factor receptor 1 amplification is also a common genetic event in head and neck squamous cell carcinoma. For this purpose, we assembled a cohort of 555 patients, including 264 with metastatic disease and 147 with recurrent disease. Formalin-fixed, paraffin-embedded material of primary tumors, metastases and recurrences were assessed for fibroblast growth factor receptor 1 copy number status using fluorescence in situ hybridization. Human papilloma virus status was detected by p16 immunohistochemistry staining and PCR-ELISA. Molecular parameters were correlated with each other and with clinicopathological data. We found 15% of primary head and neck squamous cell carcinoma to display a fibroblast growth factor receptor 1 amplification. In nearly all cases, metastatic and recurrent tumor samples shared the same amplification status as the corresponding primary tumor. Fibroblast growth factor receptor 1 amplification was associated with nicotine and alcohol consumption, but was mutually exclusive with human papilloma virus infection. Amplification of the gene was associated with parameters of worse outcome. Our data identify fibroblast growth factor receptor 1 amplification as a frequent event in primary and metastatic head and neck squamous cell carcinoma and represents a potential biomarker for more aggressive disease. Fibroblast growth factor receptor 1-amplified tumors could potentially comprise a subset of head and neck squamous cell carcinoma against which targeted small-molecule inhibitors hold therapeutic efficacy.

621 A Phase I Dose-escalation Study of MFGR1877S, a Human Monoclonal Anti-fibroblast Growth Factor Receptor 3 (FGFR3) Antibody, in Patients (pts) with Advanced Solid Tumors

621 A Phase I Dose-escalation Study of MFGR1877S, a Human Monoclonal Anti-fibroblast Growth Factor Receptor 3 (FGFR3) Antibody, in Patients (pts) with Advanced Solid Tumors

Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma

Fibroblast growth factor receptor 2 is a member of receptor tyrosine kinase family, and fibroblast growth factor receptor 2 gene amplification or missense mutation has been observed in various human cancers, including gastric carcinoma. Recent studies have shown that anti-fibroblast growth factor receptor 2 agents inhibit tumor progression in various human cancers, such as endometrial carcinoma and gastric carcinoma, which remains one of the most frequent causes of cancer-related death worldwide. We considered that knowledge of the status of fibroblast growth factor receptor 2 gene amplification in gastric carcinoma might aid in targeted cancer therapy. In this study, fibroblast growth factor receptor 2 amplification status was evaluated by fluorescence in situ hybridization in 313 surgically resected gastric carcinoma tissues, and the results were validated by quantitative real-time polymerase chain reaction. In addition, potential associations between clinicopathologic parameters and the presence of fibroblast growth factor receptor 2 amplification were investigated, and survival analysis was performed. Of the 313 cases, 14 (4.5%) showed fibroblast growth factor receptor 2 amplification by fluorescence in situ hybridization. Fibroblast growth factor receptor 2 amplification was found to be associated with a higher pT stage (P = .023), higher pN stage (P = .038), and distant metastasis (P = .009) and to be significantly associated with lower cancer-specific survival by univariate analysis (P = .012). Gastric carcinoma with fibroblast growth factor receptor 2 amplification was found to be associated with advanced disease and a poor prognosis. We believe that the determination of fibroblast growth factor receptor 2 amplification status could allow the identification of a subset of cancers sensitive to targeted fibroblast growth factor receptor 2 inhibitor-based therapy.