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https://www.readbyqxmd.com/read/29525380/prognostic-effect-of-fgfr-mutations-or-gene-fusions-in-patients-with-metastatic-urothelial-carcinoma-receiving-first-line-platinum-based-chemotherapy-results-from-a-large-single-institution-cohort
#1
Andrea Necchi, Salvatore Lo Vullo, Daniele Raggi, Annunziata Gloghini, Patrizia Giannatempo, Maurizio Colecchia, Luigi Mariani
FGFR gene alterations represent a target for treatment in clinical trials of urothelial carcinoma (UC). Little is known about their prognostic effect in patients with metastatic UC. We analyzed data for 112 patients treated with platinum-based first-line chemotherapy at our center between October 2011 and March 2017 and who were screened for the presence of FGFR mutations or gene fusions within multiple clinical trials with pan-FGFR inhibitors. Centralized targeted exome sequencing analyses were performed to detect multiple FGFR mutations and fusions...
March 7, 2018: European Urology Focus
https://www.readbyqxmd.com/read/29463565/an-fgfr3-myc-positive-feedback-loop-provides-new-opportunities-for-targeted-therapies-in-bladder-cancers
#2
Mélanie Mahe, Florent Dufour, Hélène Neyret-Kahn, Aura Moreno-Vega, Claire Beraud, Mingjun Shi, Imene Hamaidi, Virginia Sanchez-Quiles, Clementine Krucker, Marion Dorland-Galliot, Elodie Chapeaublanc, Remy Nicolle, Hervé Lang, Celio Pouponnot, Thierry Massfelder, François Radvanyi, Isabelle Bernard-Pierrot
FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an FGFR3 mutation...
February 20, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29354493/different-stages-in-drug-development-for-muscle-invasive-bladder-cancer
#3
REVIEW
Gallus Beatus Ineichen, Raphael Röthlisberger, Kevin Fabian Johner, Roland Seiler
Muscle-invasive bladder cancer (MIBC) is a highly aggressive disease. Despite optimal therapy, half of the patients will succumb to disease. This prognosis could not be improved over the last three decades. Therefore, MIBC is left behind from other cancers such as prostate, where novel treatment options were discovered and improve patient outcomes. While being aware of the recent emerging evidence of checkpoint inhibition in MIBC, we aim to describe different stages of drug development in MIBC by using three specific targets...
December 2017: Translational Andrology and Urology
https://www.readbyqxmd.com/read/29222162/dual-inhibition-of-pik3c3-and-fgfr-as-a-new-therapeutic-approach-to-treat-bladder-cancer
#4
Chun-Han Chen, Chun A Changou, Tsung-Han Hsieh, Yu-Ching Lee, Cheng-Ying Chu, Kai-Cheng Hsu, Hao-Ching Wang, Yu-Chen Lin, Yan-Ni Lo, Yun-Ru Liu, Jing-Ping Liou, Yun Yen
Purpose: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms. Experimental Design: Autophagy flux, morphology, and intracellular organelles were evaluated by Western blotting, transmission electron microscope, and fluorescence microscope. Molecular docking and surface plasmon resonance assay were performed to identify drug-protein interaction...
March 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29207153/fgfr-inhibitor-bgj398-and-hdac-inhibitor-obp-801-synergistically-inhibit-cell-growth-and-induce-apoptosis-in-bladder-cancer-cells
#5
Toshiya Takamura, Mano Horinaka, Shusuke Yasuda, Seijiro Toriyama, Yuichi Aono, Yoshihiro Sowa, Tsuneharu Miki, Osamu Ukimura, Toshiyuki Sakai
In advanced bladder cancer, cisplatin-based chemotherapy has been the standard treatment for many years, but there are many problems in terms of side-effects. Recently, a number of clinical trials using molecular-targeted agents have been conducted, and new therapies are expected that could replace conventional cytotoxic chemotherapy. We herein report that concurrent treatment with fibroblast growth factor receptor (FGFR) inhibitor BGJ398 and the novel histone deacetylase (HDAC) inhibitor OBP-801/YM753/spiruchostatin A synergistically inhibited cell growth and markedly induced apoptosis in high-grade bladder cancer cells...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/28930565/role-of-fibroblast-growth-factor-receptor-2-splicing-in-normal-and-cancer-cells
#6
Toshiyuki Ishiwata
Types 1-4 of fibroblast growth factor receptors (FGFR) are all expressed in various cancers. Because of its prominent role in carcinogenesis and cancer progression, FGFR-2, is being considered as a novel target in cancer treatment. Owing to the alternative splicing of its extracellular domain, FGFR-2 exists in two variants: IIIb and IIIc. FGFR-2 IIIb is mainly expressed in normal epithelial cells, as well as in oral mucosal, esophageal, gastric, colorectal, pancreatic, pulmonary, breast, endometrial, cervical, and prostate cancers...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28665128/discovery-of-the-irreversible-covalent-fgfr-inhibitor-8-3-4-acryloylpiperazin-1-yl-propyl-6-2-6-dichloro-3-5-dimethoxyphenyl-2-methylamino-pyrido-2-3-d-pyrimidin-7-8h-one-prn1371-for-the-treatment-of-solid-tumors
#7
Ken A Brameld, Timothy D Owens, Erik Verner, Eleni Venetsanakos, J Michael Bradshaw, Vernon T Phan, Danny Tam, Kwan Leung, Jin Shu, Jacob LaStant, David G Loughhead, Tony Ton, Dane E Karr, Mary E Gerritsen, David M Goldstein, Jens Oliver Funk
Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition...
August 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28521156/2-oxo-3-4-dihydropyrimido-4-5-d-pyrimidinyl-derivatives-as-new-irreversible-pan-fibroblast-growth-factor-receptor-fgfr-inhibitors
#8
Xueqiang Li, Christopher P Guise, Rana Taghipouran, Yuliana Yosaatmadja, Amir Ashoorzadeh, Woo-Kyong Paik, Christopher J Squire, Shuang Jiang, Jinfeng Luo, Yong Xu, Zheng-Chao Tu, Xiaoyun Lu, Xiaomei Ren, Adam V Patterson, Jeff B Smaill, Ke Ding
A series of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were designed and synthesized as new irreversible inhibitors of the FGFR family. One of the most promising compounds 2l potently inhibited FGFR1/2/3 with IC50 values of 1.06, 0.84 and 5.38 nM, respectively, whereas its potency against FGFR4 was diminished by an order of magnitude. Compound 2l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung cancer cells, FGFR2-amplified SUM52 breast cancer cells and FGFR3-amplified SW780 bladder cancer cells with low nanomolar IC50 values, but was significantly less potent against four FGFR-negative cancer cell lines, with low micromolar IC50 values...
July 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28515962/analyses-of-publicly-available-genomics-resources-define-fgf-2-expressing-bladder-carcinomas-as-emt-prone-proliferative-tumors-with-low-mutation-rates-and-high-expression-of-ctla-4-pd-1-and-pd-l1
#9
Elizabeth A McNiel, Philip N Tsichlis
FGF-2 is overexpressed in a subset of invasive bladder carcinomas and its overexpression correlates with poor prognosis. Analyses of publicly available databases addressing the molecular mechanisms that may be responsible for the poor prognosis of these tumors, revealed that FGF-2 expression correlates positively with the expression of EMT-promoting transcription factors and with changes in gene expression that are characteristic of EMT. The same analyses also revealed that FGF-2 correlates negatively with the expression, mutation and copy number variations of FGFR-3, all of which are associated with non-invasive bladder carcinomas...
2017: Signal Transduction and Targeted Therapy
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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