Fibroblast growth factor receptor 1 as a putative therapy target in colorectal cancer.

Digestion. 88(3):172–181.

Göke F, Göke A, von Mässenhausen A, Franzen A, Sharma R, Kirsten R, Böhm D, Kristiansen G, Stenzinger A, Wynes M, Hirsch FR, Weichert W, Heasley L, Buettner R, Perner S (2013).
PMID: 24135816 | DOI: 10.1159/000355018

BACKGROUND/AIMS: Resembling a potential therapeutic drug target, fibroblast growth factor receptor 1 (FGFR1) amplification and expression was assessed in 515 human colorectal cancer (CRC) tissue samples, lymph node metastases and CRC cell lines. METHODS: FGFR1 amplification status was determined using fluorescence in situ hybridization. Additionally, we assessed protein levels employing Western blots and immunohistochemistry. The FGFR1 mRNA localization was analyzed using mRNA in situ hybridization. Functional studies employed the FGFR inhibitor NVP-BGJ398. RESULTS: Of 454 primary CRCs, 24 displayed FGFR1 amplification. 92/94 lymph node metastases presented the same amplification status as the primary tumor. Of 99 investigated tumors, 18 revealed membranous activated pFGFR1 protein. FGFR1 mRNA levels were independent of the amplification status or pFGFR1 protein occurrence. In vitro, a strong antiproliferative effect of NVP-BGJ398 could be detected in cell lines exhibiting high FGFR1 protein. CONCLUSION: FGFR1 is a potential therapeutic target in a subset of CRC. FGFR1 protein is likely to represent a central factor limiting the efficacy of FGFR inhibitors. The lack of correlation between its evaluation at genetic/mRNA level and its protein occurrence indicates that the assessment of the receptor at an immunohistochemical level most likely represents a suitable way to assess FGFR1 as a predictive biomarker for patient selection in future clinical trials.

Fibroblast Growth Factor Receptor 1 and Related Ligands in Small-Cell Lung Cancer.

J Thorac Oncol. 2015 May 27.

Zhang L, Yu H, Badzio A, Boyle TA, Schildhaus HU, Lu X, Dziadziuszko R, Jassem J, Varella-Garcia M, Heasley LE, Kowalewski AA, Ellison K, Chen G, Zhou C, Hirsch FR.
PMID: 26016563 | DOI: 10.1080/15476286.2015.1053687

Introduction: Small-cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been understudied for novel therapies. Signaling through fibroblast growth factors (FGF2, FGF9) and their high-affinity receptor has recently emerged as a contributing factor in the pathogenesis and progression of non-small-cell lung cancer. In this study, we evaluated fibroblast growth factor receptor 1 (FGFR1) and ligand expression in primary SCLC samples. Methods: FGFR1 protein expression, messenger RNA (mRNA) levels, and gene copy number were determined by immunohistochemistry (IHC), mRNA in situ hybridization, and silver in situ hybridization, respectively, in primary tumors from 90 patients with SCLC. Protein and mRNA expression of the FGF2 and FGF9 ligands were determined by IHC and mRNA in situ hybridization, respectively. In addition, a second cohort of 24 SCLC biopsy samples with known FGFR1 amplification by fluorescence in situ hybridization was assessed for FGFR1 protein expression by IHC. Spearman correlation analysis was performed to evaluate associations of FGFR1, FGF2 and FGF9 protein levels, respective mRNA levels, and FGFR1 gene copy number. Results: FGFR1 protein expression by IHC demonstrated a significant correlation with FGFR1 mRNA levels (p < 0.0001) and FGFR1 gene copy number (p = 0.03). The prevalence of FGFR1 mRNA positivity was 19.7%. FGFR1 mRNA expression correlated with both FGF2 (p = 0.0001) and FGF9 (p = 0.002) mRNA levels, as well as with FGF2 (p = 0.01) and FGF9 (p = 0.001) protein levels. There was no significant association between FGFR1 and ligands with clinical characteristics or prognosis. In the second cohort of specimens with known FGFR1 amplification by fluorescence in situ hybridization, 23 of 24 had adequate tumor by IHC, and 73.9% (17 of 23) were positive for FGFR1 protein expression. Conclusions: A subset of SCLCs is characterized by potentially activated FGF/FGFR1 pathways, as evidenced by positive FGF2, FGF9, and FGFR1 protein and/or mRNA expression. FGFR1 protein expression is correlated with FGFR1 mRNA levels and FGFR1 gene copy number. Combined analysis of FGFR1 and ligand expression may allow selection of patients with SCLC to FGFR1 inhibitor therapy.

FGFR1 expression levels predict BGJ398-sensitivity of FGFR1-dependent head and neck squamous cell cancers

Clin Cancer Res. 2015 May 26.

GÃ¶ke F, Franzen A, Hinz TK, Marek LA, Yoon P, Sharma R, Bode M, von MÃ¤ssenhausen A, Lankat-Buttgereit B, GÃ¶ke A, Golletz C, Kirsten R, Boehm D, Vogel W, Kleczko EK, Eagles J, Hirsch FR, Van Bremen T, Bootz F, SchrÃ¶ck A, Kim J, Tan AC, Jimeno A, Heasle
PMID: 26027736 | DOI: 10.1038/ncomms8222.

Background: FGFR1 copy number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors and patient-derived xenografts (PDXs) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398. Methods: FGFR1 status, expression levels and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n=353) were assessed for FGFR1 CNG and mRNA levels and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n=39) were submitted to FGFR1 copy number detection and mRNA assays to identify putative FGFR1-dependent tumors. Results: Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. 31% of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The non-amplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398. Conclusion: FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts TKI sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC.

FGFR1 mRNA and Protein Expression, not Gene Copy Number, Predict FGFR TKI Sensitivity Across All Lung Cancer Histologies

Clin Cancer Res. 2014 Apr 25.

Wynes MW, Hinz TK, Gao D, Martini M, Marek L, Ware KE, Edwards MG, Bohm D, Perner S, Helfrich BA, Dziadziuszko R, Jassem J, Wojtylak S, Sejda A, Gozgit JM, Bunn Jr PA, Camidge DR, Tan AC, Hirsch FR, Heasley LE (2014)
PMID: 24771645

Purpose: FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous-cell lung cancers (SCC). The exclusive use of FGFR1 GCN for predicting FGFR TKI sensitivity assumes increased GCN is the only mechanism for biologically-relevant increases in FGFR1 signaling. Herein, we tested whether FGFR1 mRNA and protein expression may serve as better biomarkers of FGFR TKI sensitivity in lung cancer. Experimental Design: Histologically diverse lung cancer cell lines were submitted to assays for ponatinib sensitivity, a potent FGFR TKI. A tissue microarray comprised of resected lung tumors was submitted to FGFR1 GCN and mRNA analyses and the results were validated with TCGA lung cancer data. Results: 14/58 cell lines exhibited ponatinib sensitivity (IC50 values < 50 nM) that correlated with FGFR1 mRNA and protein expression, but not with FGFR1 GCN or histology. Moreover, ponatinib sensitivity associated with mRNA expression of the ligands, FGF2 and FGF9. In resected tumors, 22% of adenocarcinomas and 28% of SCCs expressed high FGFR1 mRNA. Importantly, only 46% of SCCs with increased FGFR1 GCN expressed high mRNA. Lung cancer TCGA data validated these findings and unveiled overlap of FGFR1 mRNA positivity with KRAS and PIK3CA mutations. Conclusions: FGFR1 dependency is frequent across various lung cancer histologies and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN. The study provides important and timely insight into clinical testing of FGFR TKIs in lung cancer and other solid tumor types.

Preselection of lung cancer cases using FGFR1 mRNA and gene copy number for treatment with ponatinib.

Clinical Lung Cancer

2018 Sep 03

Ng TL, Yu H, Smith DE, Boyle TA, York ER, Leedy S, Gao D, Aisner DL, Van Bokhoven A, Heasley LE, Hirsch FR, Camidge DR.
PMID: - | DOI: 10.1016/j.cllc.2018.09.001

Abstract

Introduction

Pre-clinically, high FGFR1 mRNA (FGFR1-MRNA) and FGFR1 amplification (FGFR1-AMP) predicted sensitivity to FGFR inhibitors in NSCLC and SCLC cell lines. KRAS mutations did not preclude sensitivity.

Patients and Methods

Metastatic EGFR- and ALK-negative lung cancers were screened for FGFR1-MRNA by in-situ hybridization (ISH) and FGFR1-AMP by silver in-situ hybridization (SISH). Positive cases were offered ponatinib, a multi-kinase inhibitor of FGFR1-4. Differences in overall survival (OS) between cohorts were assessed using log-rank test. Association of FGFR1 positivity with clinicopathologic features were assessed using Fisher’s exact test and Kruskal-Wallis rank sum test.

Results

171 cases were prescreened: 9/123 (7.3%) SISH+; 53/126 (42.1%) ISH+; 6 cases concordantly positive for SISH and ISH. SISH+ cases had fewer coincident KRAS mutations (p=0.03) than SISH- cases, and ISH+ cases had worse OS (p=0.020) than ISH- cases. Data distributions suggested a distinct higher positivity cutpoint for FGFR1 ISH (≥20%), occurring in 23% [29/126] cases, was associated with SCLC histology (p=0.022), soft tissue metastases (p=0.050) and shorter OS (p=0.031). Four patients received ponatinib on study: All ISH+ by the initial cutpoint, 2/4 by higher cutpoint, 1/4 SISH+. Tolerability was poor. The best response for the two higher ISH cases was SD and PD for the two lower ISH cases.

Conclusions

Elevated FGFR1-MRNA is more common than FGFR1-AMP and associated with worse OS. Higher FGFR1 mRNA expression may be associated with a specific phenotype and is worthy of further exploration. Ponatinib’s poor tolerance suggests further FGFR exploration in ISH+ cases should utilize more selective FGFR1 inhibitors.

Asymptomatic Middle East Respiratory Syndrome Coronavirus Infection in Rabbits.

J Virol. 2015 Mar 25.

Haagmans BL, van den Brand JM, Provacia LB, Raj VS, Stittelaar KJ, Getu S, de Waal L, Bestebroer TM, van Amerongen G, Verjans GM, Fouchier RA, Smits SL, Thijs K, Osterhaus AD.

The ability of Middle East respiratory syndrome coronavirus (MERS-CoV) to infect small animal species may be restricted given the fact that mice, ferrets and hamsters were shown to resist MERS-CoV infection. We inoculated rabbits with MERS-CoV. Although virus was detected in the lungs, neither significant histopathological changes nor clinical symptoms were observed. Infectious virus, however, was excreted from the upper respiratory tract, indicating a potential route of MERS-CoV transmission in some animal species.

An orthopoxvirus-based vaccine reduces virus excretion after MERS CoV infection in dromedary camels

Science

2015 Dec 18

Haagmans BL, van den Brand JMA, Stalin Raj V, Volz A, Wohlsein P, Smits SL, Schipper D, Bestebroer TM, Okba N, Fux R, Bensaid A, Solanes Foz D, Kuiken T, Baumgärtner W, Segalés J, Sutter G, Osterhaus ADME.
PMID: - | DOI: 10.1126/science.aad1283

Middle East respiratory syndrome coronavirus (MERS-CoV) infections cause an ongoing outbreak in humans fueled by multiple zoonotic MERS-CoV introductions from dromedary camels. Besides implementing hygiene measures to limit further camel-to-human and human-to-human transmissions, vaccine-mediated reduction of MERS-CoV spread from the animal reservoir may be envisaged. Here, we show that a modified vaccinia virus Ankara (MVA) virus vaccine expressing the MERS-CoV spike protein confers mucosal immunity in dromedary camels. Significant reduction of excreted infectious virus and viral RNA transcripts was observed in vaccinated animals upon MERS-CoV challenge as compared to controls. Protection correlated with the presence of serum neutralizing antibodies to MERS-CoV. Induction of MVA-specific antibodies that cross-neutralize camelpox virus, would also provide protection against camelpox.

Efficacy and safety of dovitinib in pretreated patients with advanced squamous non-small cell lung cancer with FGFR1 amplification: A single-arm, phase 2 study.

Cancer.

2016 Jun 17

Lim SH, Sun JM, Choi YL, Kim HR, Ahn S, Lee JY, Lee SH, Ahn JS, Park K, Kim JH, Cho BC, Ahn MJ.
PMID: 27315356 | DOI: 10.1002/cncr.30135.

Abstract

BACKGROUND:

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driving oncogene in squamous cell cancer (SCC) of the lung. The current phase 2 study evaluated the efficacy and tolerability of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung.

METHODS:

Patients with pretreated advanced SCC of the lung whose tumors demonstrated FGFR1 amplification of > 5 copies by fluorescence in situ hybridization were enrolled. Dovitinib at a dose of 500 mg was administered orally, once daily, on days 1 to 5 of every week, followed by 2 days off. The primary endpoint was overall response. Secondary endpoints were progression-free survival, overall survival, and toxicity.

RESULTS:

All 26 patients were men with a median age of 68 years (range, 52-80 years). The majority of patients were ever-smokers. The median duration of dovitinib administration (28 days per cycle) was 2.5 months (range, 0.7-8.6 months). The overall response rate was 11.5% (95% confidence interval [95% CI], 0.8%-23.8%) and the disease control rate was 50% (95% CI, 30.8%-69.2%), with 3 patients achieving partial responses. Response durations for the patients with partial responses were ≥4.5 months, ≥ 5.1 months, and 6.1 months, respectively. After a median follow-up of 15.7 months (range, 1.2-25.6 months), the median overall survival was 5.0 months (95% CI, 3.6-6.4 months) and the median progression-free survival was 2.9 months (95% CI, 1.5-4.3 months). The most common grade 3 or higher adverse events were fatigue (19.2%), anorexia (11.5%), and hyponatremia (11.5%) (event severity was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]).

A Case Report of a Middle East Respiratory Syndrome Survivor with Kidney Biopsy Results

Journal of Korean Medical Science

2016 Mar 10

Cha RH, Yang SH, Moon KC, Joh JS, Lee JY, Shin HS, Kim DK, Kim YS.
PMID: - | DOI: 10.3346/jkms.2016.31.4.635

A 68-year old man diagnosed with Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) presented with multiple pneumonic infiltrations on his chest X-ray, and the patient was placed on a mechanical ventilator because of progressive respiratory failure. Urinary protein excretion steadily increased for a microalbumin to creatinine ratio of 538.4 mg/g Cr and a protein to creatinine ratio of 3,025.8 mg/g Cr. The isotope dilution mass spectrometry traceable serum creatinine level increased to 3.0 mg/dL. We performed a kidney biopsy 8 weeks after the onset of symptoms. Acute tubular necrosis was the main finding, and proteinaceous cast formation and acute tubulointerstitial nephritis were found. There were no electron dense deposits observed with electron microscopy. We could not verify the virus itself by in situ hybridization and confocal microscopy (MERS-CoV co-stained with dipeptidyl peptidase 4). The viremic status, urinary virus excretion, and timely kidney biopsy results should be investigated with thorough precautions to reveal the direct effects of MERS-CoV with respect to renal complications.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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