A Decade of FGF Receptor Research in Bladder Cancer: Past, Present, and Future Challenges
TL;DR: Overall, FGFRs hold promise as therapeutic targets, diagnostic and prognostic markers, and screening tools for early detection and clinical management of UC.
Abstract: Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFRs) and activating downstream signalling pathways, including RAS/MAPK, PLCγ1, PI3K, and STATs. In the last ten years, it has become clear that FGF signalling is altered in a high proportion of bladder tumours. Activating mutations and/or overexpression of FGFR3 are common in urothelial tumours with low malignant potential and low-stage and -grade urothelial carcinomas (UCs) and are associated with a lower risk of progression and better survival in some subgroups. FGFR1 is not mutated in UC, but overexpression is frequent in all grades and stages and recent data indicate a role in urothelial epithelial-mesenchymal transition. In vitro and in vivo studies have shown that FGFR inhibition has cytotoxic and/or cytostatic effects in FGFR-dependent bladder cancer cells and FGFR-targeted agents are currently being investigated in clinical studies for the treatment of UC. Urine-based tests detecting common FGFR3 mutations are also under development for surveillance of low-grade and -stage tumours and for general population screening. Overall, FGFRs hold promise as therapeutic targets, diagnostic and prognostic markers, and screening tools for early detection and clinical management of UC.
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TL;DR: FGFR aberrations are common in a wide variety of cancers, with the majority being gene amplifications or activating mutations, and data suggest that FGFR inhibition could be an important therapeutic option across multiple tumor types.
Abstract: Purpose: Molecular profiling may have prognostic and predictive value, and is increasingly used in the clinical setting. There are more than a dozen fibroblast growth factor receptor (FGFR) inhibitors in development. Optimal therapeutic application of FGFR inhibitors requires knowledge of the rates and types of FGFR aberrations in a variety of cancer types. Experimental Design: We analyzed frequencies of FGFR aberrations in 4,853 solid tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One. Results: FGFR aberrations were found in 7.1% of cancers, with the majority being gene amplification (66% of the aberrations), followed by mutations (26%) and rearrangements (8%). FGFR1 (mostly amplification) was affected in 3.5% of 4,853 patients; FGFR2 in 1.5%; FGFR3 in 2.0%; and FGFR4 in 0.5%. Almost every type of malignancy examined showed some patients with FGFR aberrations, but the cancers most commonly affected were urothelial (32% FGFR-aberrant); breast (18%); endometrial (∼13%), squamous lung cancers (∼13%), and ovarian cancer (∼9%). Among 35 unique FGFR mutations seen in this dataset, all but two are found in COSMIC. Seventeen of the 35 are known to be activating, and 11 are transforming. Conclusions: FGFR aberrations are common in a wide variety of cancers, with the majority being gene amplifications or activating mutations. These data suggest that FGFR inhibition could be an important therapeutic option across multiple tumor types. Clin Cancer Res; 22(1); 259–67. ©2015 AACR.
503 citations
Cites background from "A Decade of FGF Receptor Research i..."
...Di Martino and colleagues showed that the most common FGFR3 mutations seen in urothelial cancers are able to transform NIH-3T3 cells, but have less potent effects on normal bladder cells (TERT-NHUC) (13)....
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...For instance, FGFR3 mutations are seen in >50% of bladder cancer cases with low-grade, noninvasive disease, but drop in frequency, once one looks at higher grade/stage (13)....
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TL;DR: As urothelial cell lines with FGFR3 fusions are extremely sensitive to FGFR-selective agents, the presence of a fusion gene may aid in selection of patients forFGFR-targeted therapy.
Abstract: FGF receptor 3 (FGFR3) is activated by mutation or over-expression in many bladder cancers. Here, we identify an additional mechanism of activation via chromosomal re-arrangement to generate constitutively activated fusion genes. FGFR3–transforming acid coiled coil 3 (TACC3) fusions resulting from 4p16.3 re-arrangements and a t(4;7) that generates a FGFR3-BAI1-associated protein 2-like 1 (BAIAP2L1) fusion were identified in 4 of 43 bladder tumour cell lines and 2 of 32 selected tissue samples including the tumour from which one of the cell lines was derived. These are highly activated and transform NIH-3T3 cells. The FGFR3 component is identical in all cases and lacks the final exon that includes the phospholipase C gamma 1 (PLCγ1) binding site. Expression of the fusions in immortalized normal human urothelial cells (NHUC) induced activation of the mitogen-activated protein kinase pathway but not PLCγ1. A protein with loss of the terminal region alone was not as highly activated as the fusion proteins, indicating that the fusion partners are essential. The TACC3 fusions retain the TACC domain that mediates microtubule binding and the BAIAP2L1 fusion retains the IRSp53/MIM domain (IMD) that mediates actin binding and Rac interaction. As urothelial cell lines with FGFR3 fusions are extremely sensitive to FGFR-selective agents, the presence of a fusion gene may aid in selection of patients for FGFR-targeted therapy.
357 citations
Cites background from "A Decade of FGF Receptor Research i..."
...SW780 has no normal chromosome 4; chromosome 4 which is not involved in t(4;7) is involved in an apparently balanced t(1;4)(q11;q1?) with an apparently intact 4p....
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...FGFR3 is implicated as an oncogene in the majority ( 80%) of low-grade non-invasive (stage Ta) bladder tumours and its upregulated expression in 40% of invasive bladder tumours implies that it also plays an oncogenic role in these (1)....
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TL;DR: The structurally and biophysically derived mechanisms of FGF signaling are discussed, and how the insights gained may guide the development of therapies for treatment of a diverse array of human diseases is discussed.
Abstract: Fibroblast growth factors (FGFs) signal in a paracrine or endocrine fashion to mediate a myriad of biological activities, ranging from issuing developmental cues, maintaining tissue homeostasis, and regulating metabolic processes. FGFs carry out their diverse functions by binding and dimerizing FGF receptors (FGFRs) in a heparan sulfate (HS) cofactor- or Klotho coreceptor-assisted manner. The accumulated wealth of structural and biophysical data in the past decade has transformed our understanding of the mechanism of FGF signaling in human health and development, and has provided novel concepts in receptor tyrosine kinase (RTK) signaling. Among these contributions are the elucidation of HS-assisted receptor dimerization, delineation of the molecular determinants of ligand-receptor specificity, tyrosine kinase regulation, receptor cis-autoinhibition, and tyrosine trans-autophosphorylation. These structural studies have also revealed how disease-associated mutations highjack the physiological mechanisms of FGFR regulation to contribute to human diseases. In this paper, we will discuss the structurally and biophysically derived mechanisms of FGF signaling, and how the insights gained may guide the development of therapies for treatment of a diverse array of human diseases.
195 citations
Cites background from "A Decade of FGF Receptor Research i..."
...…(Dode et al. 2003; Pitteloud et al. 2006a), hearing loss (Tekin et al. 2007, 2008), and renal phosphate wasting disorders (Shimada et al. 2001; White et al. 2001), as well as many acquired forms of cancers (Rand et al. 2005; Pollock et al. 2007; Gartside et al. 2009; di Martino et al. 2012)....
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TL;DR: Comprehensive NGS of 35 UCs of the bladder revealed a diverse spectrum of actionable GAs in 83% of cases, which has the potential to inform treatment decisions for patients with relapsed and metastatic disease.
130 citations
TL;DR: Collectively, these novel therapeutic targets and treatment strategies hold promise to improve the outcome of patients afflicted with this malignancy.
113 citations
Cites background from "A Decade of FGF Receptor Research i..."
...These mutations are commonly located in exons 7, 10 and 15 encoding the extracellular domain of the receptor causing ligand-independent receptor activation [24]....
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References
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01 Jan 1987
TL;DR: Head and Neck Tumours.- Lip and Oral Cavity.- Pharynx.- Larynx.' Maxillary Sinus.- Salivary Glands.- Thyroid Gland.- Digestive System Tumour .
Abstract: Head and Neck Tumours.- Lip and Oral Cavity.- Pharynx.- Larynx.- Maxillary Sinus.- Salivary Glands.- Thyroid Gland.- Digestive System Tumours.- Oesophagus.- Stomach.- Colon and Rectum.- Anal Canal.- Liver.- Gall Bladder.- Extrahepatic Bile Ducts.- Ampulla of Vater.- Pancreas.- Lung Tumours.- Tumours of Bone and Soft Tissues.- Bone.- Soft Tissue.- Skin Tumours.- Carcinoma of Skin.- Melanoma of Skin.- Breast Tumours.- Gynaecological Tumours.- Cervix Uteri.- Corpus Uteri.- Ovary.- Vagina.- Vulva.- Urological Tumours.- Prostate.- Testis.- Penis.- Urinary Bladder.- Kidney.- Renal Pelvis and Ureter.- Urethra.- Ophthalmic Tumours.- Carcinoma of Eyelid.- Malignant Melanoma of Eyelid.- Carcinoma of Conjunctiva.- Malignant Melanoma of Conjunctiva.- Malignant Melanoma of Uvea.- Retinoblastoma.- Sarcoma of Orbit.- Carcinoma of Lacrimal Gland.- Brain Tumours.- Hodgkin's Disease.- Non-Hodgkin's Lymphoma.- Paediatric Tumours.- Nephroblastoma (Wilms' Tumour).- Neuroblastoma.- Soft Tissue Sarcomas - Paediatric.
15,624 citations
TL;DR: The American Cancer Society as mentioned in this paper estimated the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data regarding cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from National Center for Health Statistics.
Abstract: Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data regarding cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,529,560 new cancer cases and 569,490 deaths from cancer are projected to occur in the United States in 2010. Overall cancer incidence rates decreased in the most recent time period in both men (1.3% per year from 2000 to 2006) and women (0.5% per year from 1998 to 2006), largely due to decreases in the 3 major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and 2 major cancer sites in women (breast and colorectum). This decrease occurred in all racial/ethnic groups in both men and women with the exception of American Indian/Alaska Native women, in whom rates were stable. Among men, death rates for all races combined decreased by 21.0% between 1990 and 2006, with decreases in lung, prostate, and colorectal cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2006 decreased by 12.3%, with decreases in breast and colorectal cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates translates to the avoidance of approximately 767,000 deaths from cancer over the 16-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment. CA Cancer J Clin 2010;60:277-300. © 2010 American Cancer Society, Inc.
11,920 citations
01 Jan 2002
7,963 citations
"A Decade of FGF Receptor Research i..." refers background or methods in this paper
...In western countries, around 90% of bladder tumours are transitional cell carcinoma, with rare cases of squamous cell carcinoma and adenocarcinoma [2]....
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...Bladder tumours are classified using the TNM classification system [3] according to their invasiveness (stage Ta: confined to the urothelium; T1: invading the lamina propria; T2: invading the muscular layer; T3: invading the submuscular layers; T4: disseminating to other organs) and their differentiation state (1973 WHO grading system: grade 1, 2, or 3 [4]; 2004 WHO grading system: PUNLMP: papillary urothelial neoplasm of low-malignant potential, low grade: well-differentiated neoplasms, high grade: poorly differentiated neoplasms [2])....
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01 Jan 2004
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