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Fgfr inhibitor

Karin Bauer, Daniela Berger, Christoph C Zielinski, Peter Valent, Thomas W Grunt
In recent years, numerous new targeted drugs, including multi-kinase inhibitors and epigenetic modulators have been developed for cancer treatment. Ponatinib blocks a variety of tyrosine kinases including ABL and fibroblast growth factor receptor (FGFR), and the BET bromodomain (BRD) antagonists JQ1 and dBET1 impede MYC oncogene expression. Both drugs have demonstrated substantial anti-cancer efficacy against several hematological malignancies. Solid tumors, on the other hand, although frequently driven by FGFR and/or MYC, are often unresponsive to these drugs...
May 29, 2018: Oncotarget
Carine Pecqueux, Aysenur Arslan, Martina Heller, Michael Falkenstein, Adam Kaczorowski, Yanis Tolstov, Holger Sültmann, Carsten Grüllich, Esther Herpel, Anette Duensing, Glen Kristiansen, Markus Hohenfellner, Nora M Navone, Stefan Duensing
BACKGROUND: There is mounting evidence to suggest that stromal cells play an integral role in the progression of prostate cancer (PCa). One of the most frequently altered growth factors in PCa is fibroblast growth factor-2 (FGF-2). It has previously been proposed that early stages of PCa are characterized by a primarily exogenous, that is, stromal cell-derived FGF-2 production, whereas advanced tumors rely more on an autocrine FGF-2 production. Prostate cancer progression is characterized by an increase of genomic instability including aneuploidy and structural chromosomal alterations...
June 7, 2018: Urologic Oncology
Georgios Tsironis, Dimitrios C Ziogas, Anastasios Kyriazoglou, Marita Lykka, Konstantinos Koutsoukos, Aristotelis Bamias, Meletios-Athanasios Dimopoulos
During the last years, translational research has contributed in many advances in the treatment of non-small cell lung cancer (NSCLC) discovering genetic alternations or recognizing the immuno-escape and neo-angiogenesis of lung cancer. Although the majority of these advances took place in the non-squamous histological subtype, therapeutic options for patients diagnosed with advanced squamous cell lung cancer (SqCLC) have been also enriched significantly with the addition of nab-paclitaxel in the conventional chemotherapy; the introduction of necitumumab, afatinib and erlotinib in the inhibition of epidermal growth factor receptor (EGFR) axis and of ramucirumab in the inhibition of VEGF-induced angiogenesis and last with the approvals of nivolumab, pembrolizumab atezolizumab and durvalumab soon in the promising field of immunotherapies...
April 2018: Annals of Translational Medicine
Sarah C McDermott, Christie Rodriguez-Ramirez, Sean P McDermott, Max S Wicha, Jacques E Nör
Patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) have poor prognosis with less than 1-year median survival. Platinum-based chemotherapy remains the first-line treatment for HNSCC. The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self renewing cell populations that constitute the bulk of the tumor. A small population of CSC exists within HNSCC that are relatively resistant to chemotherapy and clinically predicted to contribute to tumor recurrence...
May 18, 2018: Oncotarget
Sumanta K Pal, Jonathan E Rosenberg, Jean H Hoffman-Censits, Raanan Berger, David I Quinn, Matthew D Galsky, Juergen Wolf, Christian Dittrich, Bhumsuk Keam, Jean-Pierre Delord, Jan H M Schellens, Gwenaëlle Gravis, Jacques Medioni, Pablo Maroto, Virote Sriuranpong, Chaiyut Charoentum, Howard A Burris, Viktor Grünwald, Daniel Petrylak, Ulka Vaishampayan, Eliahu Gez, Ugo De Giorgi, Jae-Lyun Lee, Jens Voortman, Sumati Gupta, Amir Mortazavi, David J Vaughn, Randi E Isaacs, Katie Parker, Xueying Chen, Kun Yu, Dale Porter, Sunil Sharma, Diana Graus Porta, Dean F Bajorin
BGJ398, a potent and selective pan-fibroblast growth factor receptor (FGFR) antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate...
May 30, 2018: Cancer Discovery
Patrick Pilié, Elshad Hasanov, Surena F Matin, Ashley H Henriksen Woodson, Valerie D Marcott, Shelly Bird, Rebecca S Slack, Gregory N Fuller, Ian E McCutcheon, Eric Jonasch
Von Hippel-Lindau (VHL) disease is an autosomal dominant disease occurring in 1 in 35,000 births and leads to an increased risk of a phenotypically diverse array of tumor types including, but not limited to, clear cell renal cell carcinoma (ccRCC) and hemangioblastomas (HBs). Previous studies of patients with VHL disease treated with the tyrosine kinase inhibitor (TKI) sunitinib did not show clinical response in HBs. Interestingly, VHL-related HBs displayed increased fibroblast growth factor receptor 3 (FGFR3) protein expression when compared to VHL-related ccRCCs...
May 4, 2018: Oncotarget
Manman Wei, Xia Peng, Li Xing, Yang Dai, Ruimin Huang, Meiyu Geng, Ao Zhang, Jing Ai, Zilan Song
Starting from the phase II clinical FGFR inhibitor lucitanib (2), we conducted a medicinal chemistry approach by opening the central quinoline skeleton coupled with a scaffold hopping process thus leading to a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives. Compound 25a was identified to show selective and equally high potency against FGFR1/2 and VEGFR2 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2 aberrant cancer cells were observed...
May 15, 2018: European Journal of Medicinal Chemistry
Brian R Untch, Vanessa Dos Anjos, Maria E R Garcia-Rendueles, Jeffrey A Knauf, Gnana P Krishnamoorthy, Mahesh Saqcena, Umeshkumar K Bhanot, Nicholas D Socci, Alan L Ho, Ronald Ghossein, James A Fagin
Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated in vitro by selective RTK (i...
May 14, 2018: Cancer Research
Yichao Wan, Shengzhuo He, Wei Li, Zilong Tang
Currently, cancer continues being a dramatically increasing and serious threat to public health. Although many anti-tumor agents have been developed in recent years, the survival rate of patients is not satisfactory. The poor prognosis of cancer patients is closely related to the occurrence of drug resistance. Therefore, it is urgent to develop new anti-tumor agents to make up for the deficiency. Indazoles is an important class of heterocyclic compounds possessing a variety of biological activities, such as anti-tumor, anti-bacterial, anti-inflammatory, anti-depressant and anti-hypertensive...
May 9, 2018: Anti-cancer Agents in Medicinal Chemistry
Clare E Weeden, Casey Ah-Cann, Aliaksei Z Holik, Julie Pasquet, Jean-Marc Garnier, Delphine Merino, Guillaume Lessene, Marie-Liesse Asselin-Labat
Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells...
May 10, 2018: Oncogene
Sergei Boichuk, Pavel Dunaev, Aigul Galembikova, Ilshat Mustafin, Elena Valeeva
The acquired resistance of gastrointestinal stromal tumors (GISTs) to the targeted-based therapy remains the driving force to identify the novel approaches that are capable of increasing the sensitivity of GISTs to the current therapeutic regimens. Our present data show that BGJ398, a selective fibroblast growth factor receptor (FGFR) inhibitor, sensitizes imatinib (IM)-resistant GIST cells with receptor tyrosine kinase (RTK) switch (loss of c-KIT/gain of pFGFR2a) to the low doses of topoisomerase II inhibitors - doxorubicin (Dox) and etoposide (Eto)...
July 2018: Anti-cancer Drugs
Franziska Kappert, Sridhar Sreeramulu, Hendrik R A Jonker, Christian Richter, Vladimir V Rogov, Ewgenij Proschak, Bruno Hargittay, Krishna Saxena, Harald Schwalbe
The interaction of fibroblast growth factors (FGFs) with their fibroblast growth factor receptors (FGFRs) are important in the signaling network of cell growth and development. SSR128129E (SSR), a ligand of small molecular weight with potential anti-cancer properties, acts allosterically on the extracellular domains of FGFRs. Up to now, the structural basis of SSR binding to the D3 domain of FGFR remained elusive. This work reports the structural characterization of the interaction of SSR with one specific receptor, FGFR3, by NMR spectroscopy...
June 4, 2018: Chemistry: a European Journal
Taichi Miura, Mayumi Fujita, Mitsuko Kawano, Kaori Imadome, Takeshi Yasuda, Shoko Nishihara, Toru Imamura, Mikio Masuzawa, Takashi Imai, Fumiaki Nakayama
Background and purpose: Angiosarcoma is associated with a poor prognosis and is treated with radiotherapy. Although FGF1 is a potential radioprotector, the influence of FGF1 on the malignancy of angiosarcoma remains unknown. Materials and methods: Highly stable FGF1 mutants, which exhibit stronger mitogenic activity than wild-type FGF1, were examined as strong radioprotectors and signaling agonists to clarify the effects of FGF1 on the murine angiosarcoma cell line ISOS-1...
December 2017: Clinical and Translational Radiation Oncology
Jatinder Dhami, Kim M Hirshfield, Shridar Ganesan, Mira Hellmann, Veronica Rojas, Judith K Amorosa, Gregory M Riedlinger, Hua Zhong, Siraj M Ali, Dean Pavlick, Julia A Elvin, Lorna Rodriguez-Rodriguez
FGFR - TACC fusions, including FGFR3 - TACC3 , have been identified as potential oncogenic drivers and actionable alterations in a number of different cancer types. The clinical relevance of FGFR3-TACC3 fusions in endometrial cancer has not yet been described. Formalin-fixed, paraffin-embedded metastatic endometrial carcinoma from the spleen and peritoneum were sent for comprehensive genomic profiling (CGP) using the FoundationOne platform as part of a prospective tumor genomic profiling protocol. We report the identification of an FGFR3 - TACC3 fusion in a case of metastatic endometrioid endometrial cancer...
April 2018: Cold Spring Harbor Molecular Case Studies
You-Lu Pan, Yan-Ling Liu, Jian-Zhong Chen
Fibroblast growth factor receptor 1 (FGFR1) has become a potential target for the treatment of cancer. Designing FGFR1-selective inhibitors remains fundamental to the development of anti-cancer drugs because of highly sequential homology among FGFR subtypes. In present work, four inhibitors were examined with intermolecular interaction patterns with FGFR1 and FGFR4, respectively, for the exploration of binding mechanisms by applying a combined approach of computational techniques, including flexible docking, binding site analyses, electronic structure computations, molecular dynamic simulations, and binding free energy predictions...
March 27, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Domenico Sanfelice, Hans Koss, Tom D Bunney, Gary S Thompson, Brendan Farrell, Matilda Katan, Alexander L Breeze
Fibroblast growth factors receptors (FGFR) are transmembrane protein tyrosine kinases involved in many cellular process, including growth, differentiation and angiogenesis. Dysregulation of FGFR enzymatic activity is associated with developmental disorders and cancers; therefore FGFRs have become attractive targets for drug discovery, with a number of agents in late-stage clinical trials. Here, we present the backbone resonance assignments of FGFR3 tyrosine kinase domain in the ligand-free form and in complex with the canonical FGFR kinase inhibitor PD173074...
March 26, 2018: Biomolecular NMR Assignments
Albert Grinshpun, Nancy Gavert, Roy Zvi Granit, Hadas Masuri, Ittai Ben-Porath, Shani Breuer, Aviad Zick, Shai Rosenberg, Myriam Maoz, Avital Granit, Eli Pikarsky, Ravid Strausmman, Tamar Peretz, Amir Sonnenblick
The growing use of genomic testing presents new treatment options but also new dilemmas. We describe here a heavily-pretreated metastatic triple negative breast cancer patient who failed to respond to conventional treatment. Genomic analyses were performed that discovered several targetable alterations (e.g. FGFR1, CDK6, INSR) and created a clinical challenge - which target to target first? Our solution to this relatively common scenario was using ex-vivo organ culture (EVOC) system to prioritize treatment directed toward the best molecular target...
March 22, 2018: Cancer Biology & Therapy
Gaurav Goel
Colorectal cancer (CRC) is a major public health problem in the United States with an estimated 50,260 deaths in 2017. Over the past two decades, several agents have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic CRC (mCRC). Regorafenib (BAY 73-4506) is a small-molecule multikinase inhibitor that was approved for the treatment of mCRC in 2012. This agent is a novel oral diphenylurea-based multikinase inhibitor that is active against several angiogenic receptor tyrosine kinases (RTKs; VEGFR-1, VEGFR-2, VEGFR-3, TIE-2), oncogenic RTKs (c-KIT, RET), stromal RTKs (PDGFR-B, FGFR-1), and intracellular signaling kinases (c-RAF/RAF-1, BRAF, BRAFV600E )...
2018: Cancer Management and Research
Alan Jiang, Qiufeng Liu, Ruifeng Wang, Peng Wei, Yang Dai, Xin Wang, Yechun Xu, Yuchi Ma, Jing Ai, Jingkang Shen, Jian Ding, Bing Xiong
Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5 H -pyrrolo[2,3- b ]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors...
March 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Y Jiang, H Y Chao, X W Zhang, M Zhou, X Z Lu, R Zhang, C He, Q Wang
Objective: To explore the effects and possible mechanisms of the novel pan-FGFR inhibitor BGJ398 on KG-1 cells in vitro. Methods: Effects of BGJ398 on cells proliferation were detected by CCK-8, the apoptosis was assessed by Annexin V-FITC. Reverse transcriptionquantitative polymerase chain reaction (q-PCR) analysis was used to detect the expression of apoptosis-related genes B cell lymphoma-2 (Bcl-2) and caspase-3. Western blotting analysis was performed to explore the proteins expression levels of Bcl-2, caspase-3 and the expression of p-AKT, p-S6K, p-ERK and FGFR1...
February 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
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