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https://www.readbyqxmd.com/read/28416604/oncogenic-characterization-and-pharmacologic-sensitivity-of-activating-fibroblast-growth-factor-receptor-fgfr-genetic-alterations-to-the-selective-fgfr-inhibitor-erdafitinib
#1
Jayaprakash D Karkera, Gabriela Martinez Cardona, Katherine Bell, Dana Gaffney, Joseph C Portale, Ademi Santiago-Walker, Christopher Moy, Peter King, Michael Sharp, Rastilav Bahleda, Feng R Luo, John D Alvarez, Matthew V Lorenzi, Suso J Platero
Fibroblast growth factor receptor (FGFR) genetic alterations are frequently observed in cancer, suggesting that FGFR inhibition may be a promising therapy in patients harboring these lesions.  Identification of predictive and pharmacodynamic biomarkers to select and monitor patients most likely to respond to FGFR inhibition will be the key to clinical development of this class of agents.  Sensitivity to FGFR inhibition and correlation with FGFR pathway activation status were determined in molecularly annotated panels of cancer cell lines and xenograft models...
April 17, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28255027/akt-activation-mediates-acquired-resistance-to-fibroblast-growth-factor-receptor-inhibitor-bgj398
#2
Jharna Datta, Senthilkumar Damodaran, Hannah Parks, Cristina Ocrainiciuc, Jharna Miya, Lianbo Yu, Elijah P Gardner, Eric Samorodnitsky, Michele R Wing, Darshna Bhatt, John Hays, Julie W Reeser, Sameek Roychowdhury
Activation of FGFR signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 is seen in multiple tumors, including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate the emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines...
April 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28108151/a-functional-genetic-screen-identifies-the-phosphoinositide-3-kinase-pathway-as-a-determinant-of-resistance-to-fibroblast-growth-factor-receptor-inhibitors-in-fgfr-mutant-urothelial-cell-carcinoma
#3
Liqin Wang, Tonći Šuštić, Rodrigo Leite de Oliveira, Cor Lieftink, Pasi Halonen, Marieke van de Ven, Roderick L Beijersbergen, Michel M van den Heuvel, René Bernards, Michiel S van der Heijden
Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation)...
June 2017: European Urology
https://www.readbyqxmd.com/read/27930669/development-of-rna-fish-assay-for-detection-of-oncogenic-fgfr3-tacc3-fusion-genes-in-ffpe-samples
#4
Masahiro Kurobe, Takahiro Kojima, Kouichi Nishimura, Shuya Kandori, Takashi Kawahara, Takayuki Yoshino, Satoshi Ueno, Yuichi Iizumi, Koji Mitsuzuka, Yoichi Arai, Hiroshi Tsuruta, Tomonori Habuchi, Takashi Kobayashi, Yoshiyuki Matsui, Osamu Ogawa, Mikio Sugimoto, Yoshiyuki Kakehi, Yoshiyuki Nagumo, Masakazu Tsutsumi, Takehiro Oikawa, Koji Kikuchi, Hiroyuki Nishiyama
INTRODUCTION AND OBJECTIVES: Oncogenic FGFR3-TACC3 fusions and FGFR3 mutations are target candidates for small molecule inhibitors in bladder cancer (BC). Because FGFR3 and TACC3 genes are located very closely on chromosome 4p16.3, detection of the fusion by DNA-FISH (fluorescent in situ hybridization) is not a feasible option. In this study, we developed a novel RNA-FISH assay using branched DNA probe to detect FGFR3-TACC3 fusions in formaldehyde-fixed paraffin-embedded (FFPE) human BC samples...
2016: PloS One
https://www.readbyqxmd.com/read/27870574/evaluation-of-bgj398-a-fibroblast-growth-factor-receptor-1-3-kinase-inhibitor-in-patients-with-advanced-solid-tumors-harboring-genetic-alterations-in-fibroblast-growth-factor-receptors-results-of-a-global-phase-i-dose-escalation-and-dose-expansion-study
#5
Lucia Nogova, Lecia V Sequist, Jose Manuel Perez Garcia, Fabrice Andre, Jean-Pierre Delord, Manuel Hidalgo, Jan H M Schellens, Philippe A Cassier, D Ross Camidge, Martin Schuler, Ulka Vaishampayan, Howard Burris, G Gary Tian, Mario Campone, Zev A Wainberg, Wan-Teck Lim, Patricia LoRusso, Geoffrey I Shapiro, Katie Parker, Xueying Chen, Somesh Choudhury, Francois Ringeisen, Diana Graus-Porta, Dale Porter, Randi Isaacs, Reinhard Buettner, Jürgen Wolf
Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27743530/targeting-fibroblast-growth-factor-receptors-and-immune-checkpoint-inhibitors-for-the-treatment-of-advanced-bladder-cancer-new-direction-and-new-hope
#6
REVIEW
Rafael Morales-Barrera, Cristina Suárez, Ana Martínez de Castro, Fabricio Racca, Claudia Valverde, Xavier Maldonado, Juan Maria Bastaros, Juan Morote, Joan Carles
Bladder cancer is one of the leading causes of death in Europe and the United States. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients with median overall survival of 15months and a 5-year survival rate of ⩽10%...
November 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27669755/fibroblast-growth-factor-receptor-fgfr-alterations-in-squamous-differentiated-bladder-cancer-a-putative-therapeutic-target-for-a-small-subgroup
#7
Philipp H Baldia, Angela Maurer, Timon Heide, Michael Rose, Robert Stoehr, Arndt Hartmann, Sarah V Williams, Margaret A Knowles, Ruth Knuechel, Nadine T Gaisa
Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis)...
November 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27627808/preclinical-activity-of-arq-087-a-novel-inhibitor-targeting-fgfr-dysregulation
#8
Terence G Hall, Yi Yu, Sudharshan Eathiraj, Yunxia Wang, Ronald E Savage, Jean-Marc Lapierre, Brian Schwartz, Giovanni Abbadessa
Dysregulation of Fibroblast Growth Factor Receptor (FGFR) signaling through amplifications, mutations, and gene fusions has been implicated in a broad array of cancers (e.g. liver, gastric, ovarian, endometrial, and bladder). ARQ 087 is a novel, ATP competitive, small molecule, multi-kinase inhibitor with potent in vitro and in vivo activity against FGFR addicted cell lines and tumors. Biochemically, ARQ 087 exhibited IC50 values of 1.8 nM for FGFR2, and 4.5 nM for FGFR1 and 3. In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2α, AKT, ERK) was evident by the response to ARQ 087 treatment...
2016: PloS One
https://www.readbyqxmd.com/read/27615514/proximity-labeling-reveals-molecular-determinants-of-fgfr4-endosomal-transport
#9
Ellen Margrethe Haugsten, Vigdis Sørensen, Michaela Kunova Bosakova, Gustavo Antonio de Souza, Pavel Krejci, Antoni Wiedlocha, Jørgen Wesche
The fibroblast growth factor receptors (FGFRs) are important oncogenes promoting tumor progression in many types of cancer, such as breast, bladder, and lung cancer as well as multiple myeloma and rhabdomyosarcoma. However, little is known about how these receptors are internalized and down-regulated in cells. We have here applied proximity biotin labeling to identify proteins involved in FGFR4 signaling and trafficking. For this purpose we fused a mutated biotin ligase, BirA*, to the C-terminal tail of FGFR4 (FGFR4-BirA*) and the fusion protein was stably expressed in U2OS cells...
October 7, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27563235/design-and-characteristics-of-cytotoxic-fibroblast-growth-factor-1-conjugate-for-fibroblast-growth-factor-receptor-targeted-cancer-therapy
#10
Anna Szlachcic, Malgorzata Zakrzewska, Michal Lobocki, Piotr Jakimowicz, Jacek Otlewski
Fibroblast growth factor receptors (FGFRs) are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V), was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE), and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody-drug conjugates. The FGF1V-valine-citrulline-MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE) upon cleavage by the lysosomal protease cathepsin B...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27381494/a-place-for-precision-medicine-in-bladder-cancer-targeting-the-fgfrs
#11
REVIEW
Erica di Martino, Darren C Tomlinson, Sarah V Williams, Margaret A Knowles
Bladder tumors show diverse molecular features and clinical outcome. Muscle-invasive bladder cancer has poor prognosis and novel approaches to systemic therapy are urgently required. Non-muscle-invasive bladder cancer has good prognosis, but high recurrence rate and the requirement for life-long disease monitoring places a major burden on patients and healthcare providers. Studies of tumor tissues from both disease groups have identified frequent alterations of FGFRs, including mutations of FGFR3 and dysregulated expression of FGFR1 and FGFR3 that suggest that these may be valid therapeutic targets...
October 2016: Future Oncology
https://www.readbyqxmd.com/read/27029060/trichlorobenzene-substituted-azaaryl-compounds-as-novel-fgfr-inhibitors-exhibiting-potent-antitumor-activity-in-bladder-cancer-cells-in-vitro-and-in-vivo
#12
Chun-Han Chen, Yi-Min Liu, Shiow-Lin Pan, Yun-Ru Liu, Jing-Ping Liou, Yun Yen
In the present study, we examined the antitumor activity of a series of trichlorobenzene-substituted azaaryl compounds and identified MPT0L145 as a novel FGFR inhibitor with better selectivity for FGFR1, 2 and 3. It was preferentially effective in FGFR-activated cancer cells, including bladder cancer cell lines expressing FGFR3-TACC3 fusion proteins (RT-112, RT-4). MPT0L145 decreased the phosphorylation of FGFR1, FGFR3 and their downstream proteins (FRS2, ERK and Akt). Mechanistically, cDNA microarray analysis revealed that MPT0L145 decreased genes associated cell cycle progression, and increased genes associated with autophagy pathway...
May 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/26869289/oncogenic-gene-fusion-fgfr3-tacc3-is-regulated-by-tyrosine-phosphorylation
#13
Katelyn N Nelson, April N Meyer, Asma Siari, Alexandre R Campos, Khatereh Motamedchaboki, Daniel J Donoghue
UNLABELLED: Fibroblast growth factor receptors (FGFR) are critical for cell proliferation and differentiation. Mutation and/or translocation of FGFRs lead to aberrant signaling that often results in developmental syndromes or cancer growth. As sequencing of human tumors becomes more frequent, so does the detection of FGFR translocations and fusion proteins. The research conducted in this article examines a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3), frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer...
May 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/26853465/inhibition-of-cholesterol-metabolism-underlies-synergy-between-mtor-pathway-inhibition-and-chloroquine-in-bladder-cancer-cells
#14
M A King, I G Ganley, V Flemington
Mutations to fibroblast growth factor receptor 3 (FGFR3) and phosphatase and tensin homologue (PTEN) signalling pathway components (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule inhibitors of these nodes (FGFR/PTENi) show only modest activity in preclinical models. As activation of autophagy is proposed to promote survival under FGFR/PTENi, we have investigated this relationship in a panel of 18 genetically diverse bladder cell lines. We found that autophagy inhibition does not sensitise bladder cell lines to FGFR/PTENi, but newly identify an autophagy-independent cell death synergy in FGFR3-mutant cell lines between mTOR (mammalian target of rapamycin) pathway inhibitors and chloroquine (CQ)-an anti-malarial drug used as a cancer therapy adjuvant in over 30 clinical trials...
August 25, 2016: Oncogene
https://www.readbyqxmd.com/read/26589398/novel-therapeutic-targets-in-advanced-urothelial-carcinoma
#15
REVIEW
Mathieu Rouanne, Yohann Loriot, Thierry Lebret, Jean-Charles Soria
Bladder cancer remains one of the most common and lethal diseases that cause approximately 150,000 deaths per year worldwide. Over the past two decades, the options currently available to patients with invasive disease remained essentially unchanged and no effective drugs have been approved in that time. Cisplatin-based combination chemotherapy remains the standard of care for first-line systemic treatment of metastatic urothelial carcinoma. However, the major advances in understanding the genetic background of urothelial tumors open up a new therapeutic area...
February 2016: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/26542242/the-role-of-mutations-and-overexpression-of-the-fibroblast-growth-factor-receptor-3-in-bladder-cancer
#16
REVIEW
Q Y Wang, Y Zhao, R Zhang
Bladder cancer (BC) is the seventh most common cancer worldwide. Throughout the last decade, several studies demonstrated that the fibroblast growth factor (FGF) signalling is altered in a significant proportion of patients with BC. FGF receptor (FGFR) 3 may thus serve as a promising biomarker for BC. Mutations of this gene are prevalent in BC (e.g., found in 74% of non-invasive papillary tumours), suggesting that FGFR3 status is an important event in BC. The aim of this review was to overview the outcomes of different mutations in FGFR3 receptor in the context of BC...
December 2015: Minerva Medica
https://www.readbyqxmd.com/read/26390971/targeted-therapies-in-bladder-cancer-an-overview-of-in-vivo-research
#17
REVIEW
Kim E M van Kessel, Tahlita C M Zuiverloon, Arnout R Alberts, Joost L Boormans, Ellen C Zwarthoff
Survival of patients with muscle-invasive bladder cancer is poor and new therapies are needed. Currently, none of the targeted agents that are approved for cancer therapy have been approved for the treatment of bladder cancer and the few clinical trials that have been performed had limited success, often owing to a lack of efficacy and toxic effects. However, many other novel targeted agents have been investigated in animal models of bladder cancer. EGFR, FGFR-3, VEGF, mTOR, STAT3, the androgen receptor and CD24 are molecular targets that could be efficiently inhibited, resulting in reduced tumour growth, and that have been investigated in multiple independent studies...
December 2015: Nature Reviews. Urology
https://www.readbyqxmd.com/read/26351323/tumors-with-akt1e17k-mutations-are-rational-targets-for-single-agent-or-combination-therapy-with-akt-inhibitors
#18
MULTICENTER STUDY
Barry R Davies, Nin Guan, Armelle Logie, Claire Crafter, Lyndsey Hanson, Vivien Jacobs, Neil James, Philippa Dudley, Kelly Jacques, Brendon Ladd, Celina M D'Cruz, Michael Zinda, Justin Lindemann, Makoto Kodaira, Kenji Tamura, Emma L Jenkins
AKT1(E17K) mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1(E17K) mutation is not known. Expression of exogenous copies of AKT1(E17K) in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice...
November 2015: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26293980/fibroblast-growth-factor-receptor-signaling-in-kidney-and-lower-urinary-tract-development
#19
REVIEW
Kenneth A Walker, Sunder Sims-Lucas, Carlton M Bates
Fibroblast growth factor receptors (FGFRs) and FGF ligands are highly expressed in the developing kidney and lower urinary tract. Several classic studies showed many effects of exogenous FGF ligands on embryonic renal tissues in vitro and in vivo. Another older landmark publication showed that mice with a dominant negative Fgfr fragment had severe renal dysplasia. Together, these studies revealed the importance of FGFR signaling in kidney and lower urinary tract development. With the advent of modern gene targeting techniques, including conditional knockout approaches, several publications have revealed critical roles for FGFR signaling in many lineages of the kidney and lower urinary tract at different stages of development...
June 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/26224133/fibroblast-growth-factor-receptor-signaling-in-hereditary-and-neoplastic-disease-biologic-and-clinical-implications
#20
REVIEW
Teresa Helsten, Maria Schwaederle, Razelle Kurzrock
Fibroblast growth factors (FGFs) and their receptors (FGFRs) are transmembrane growth factor receptors with wide tissue distribution. FGF/FGFR signaling is involved in neoplastic behavior and also development, differentiation, growth, and survival. FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3), and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2); intriguingly, some of these activating FGFR mutations are also seen in human cancers...
September 2015: Cancer Metastasis Reviews
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