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https://www.readbyqxmd.com/read/29017058/androgen-receptor-pathway-independent-prostate-cancer-is-sustained-through-fgf-signaling
#1
Eric G Bluemn, Ilsa M Coleman, Jared M Lucas, Roger T Coleman, Susana Hernandez-Lopez, Robin Tharakan, Daniella Bianchi-Frias, Ruth F Dumpit, Arja Kaipainen, Alexandra N Corella, Yu Chi Yang, Michael D Nyquist, Elahe Mostaghel, Andrew C Hsieh, Xiaotun Zhang, Eva Corey, Lisha G Brown, Holly M Nguyen, Kenneth Pienta, Michael Ittmann, Michael Schweizer, Lawrence D True, David Wise, Paul S Rennie, Robert L Vessella, Colm Morrissey, Peter S Nelson
Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence...
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29016732/regulation-of-vascular-smooth-muscle-cell-calcification-by-syndecan-4-fgf-2-pkc%C3%AE-signaling-and-cross-talk-with-tgf%C3%AE
#2
Samantha J Borland, Thomas G Morris, Shona C Borland, Mark R Morgan, Sheila E Francis, Catherine L R Merry, Ann E Canfield
Aims: Vascular calcification is a major cause of morbidity and mortality. Fibroblast growth factor-2 (FGF-2) plays an instructive role in osteogenesis and bone development, but its role in vascular calcification was unknown. Therefore, we investigated the involvement of FGF-2 in vascular calcification and determined the mechanism by which it regulates this process. Methods and Results: We demonstrate that FGF-2 expression is increased in vascular smooth muscle cells (VSMCs) induced to deposit a mineralized matrix by incubation with β-glycerophosphate...
September 6, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28980322/fibroblast-growth-factor-21-attenuates-calcification-of-vascular-smooth-muscle-cells-in%C3%A2-vitro
#3
Fangying Cao, Shaoping Wang, Xiangrong Cao, Xiaoxiao Liu, Kun Fu, Peng Hao, Jinghua Liu
OBJECTIVES: Vascular calcification is a dysfunction of the vasculature. Recent findings indicate that fibroblast growth factor21 (FGF21), a protector of the cardiovascular system, is related to the mineral deposition of bone and enhances the osteogenic activity of bone morphogenic protein (BMP)-2. In this study, we explored whether FGF21 suppresses vascular calcification. METHODS: A calcifying model was established by culturing primary rat vascular aortic smooth muscle cells (VSMCs) in a beta-glycerophosphate (BGP)-containing calcifying medium for 14 days...
October 4, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28978722/acquired-resistance-to-fgfr-inhibitor-in-diffuse-type-gastric-cancer-through-an-akt-independent-pkc-mediated-phosphorylation-of-gsk3%C3%AE
#4
Wen Min Lau, Eileen Teng, Kie Kyon Huang, Jin Wei Tan, Kakoli Das, Zhijiang Zang, Tania Chia, Ming Teh, Koji Kono, Wei Peng Yong, Asim Shabbir, Amy Tay, Niam Sin Phua, Patrick Tan, Shing Leng Chan, Jimmy Bok Yan So
Preclinical models of diffuse type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish diffuse type gastric cancer patient-derived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R...
October 4, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28978721/the-irreversible-covalent-fibroblast-growth-factor-receptor-inhibitor-prn1371-exhibits-sustained-inhibition-of-fgfr-after-drug-clearance
#5
Eleni Venetsanakos, Ken A Brameld, Vernon T Phan, Erik Verner, Timothy D Owens, Yan Xing, Danny Tam, Jacob LaStant, Kwan Leung, Dane E Karr, Ronald J Hill, Mary E Gerritsen, David M Goldstein, Jens Oliver Funk, J Michael Bradshaw
An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations...
October 4, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28975832/systemic-and-adjuvant-therapies-for-intrahepatic-cholangiocarcinoma
#6
Yun Shin Chun, Milind Javle
Intrahepatic cholangiocarcinoma represents the second most common primary liver cancer and is increasing in incidence. Most patients are diagnosed at an advanced, nonsurgical stage and only about 1 in 5 cases are surgically resectable. Despite surgery, the 5-year survival is low at only 30%. Multifocal, node- or margin-positive disease is at a higher risk of recurrence after resection. There is no level 1 evidence in support of postoperative adjuvant therapy. A recent adjuvant therapy phase III trial from the Partenariat de Recherche en Oncologie Digestive-Actions Concertées dans les Cancers Colo-Rectaux et Digestifs (PRODIGE) group reported no survival advantage with adjuvant gemcitabine and oxaliplatin therapy...
July 2017: Cancer Control: Journal of the Moffitt Cancer Center
https://www.readbyqxmd.com/read/28972999/effects-of-insulin-like-growth-factors-on-early-embryonic-chick-limb-myogenesis
#7
Rabeea Hazim Mohammed, Helen Anderton, John Michael Brameld, Dylan Sweetman
Limb muscles derive from pax3 expressing precursor cells that migrate from the hypaxial somite into the developing limb bud. Once there they begin to differentiate and express muscle determination genes such as MyoD. This process is regulated by a combination of inductive or inhibitory signals including Fgf18, retinoic acid, HGF, Notch and IGFs. IGFs are well known to affect late stages of muscle development and to promote both proliferation and differentiation. We examined their roles in early stage limb bud myogenesis using chicken embryos as an experimental model...
2017: PloS One
https://www.readbyqxmd.com/read/28972963/a-phase-1-study-of-arq-087-an-oral-pan-fgfr-inhibitor-in-patients-with-advanced-solid-tumours
#8
K P Papadopoulos, B F El-Rayes, A W Tolcher, A Patnaik, D W Rasco, R D Harvey, P M LoRusso, J C Sachdev, G Abbadessa, R E Savage, T Hall, B Schwartz, Y Wang, J Kazakin, W L Shaib
BACKGROUND: ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D). METHODS: Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement...
October 3, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28971553/evaluation-of-fibroblast-growth-factor-activity-exerted-by-placental-extract-used-as-a-cosmetic-ingredient
#9
Kouhei Ito, Ryuji Yamada, Nobuki Matsumoto, Toru Imamura
BACKGROUND: The biological activities claimed for placental extract (PE) in its medical and cosmetic applications are largely assumed to be the combined effects of its various signaling molecules and nutritional constituents. But there are considerable uncertainties about this assumption. AIMS: To determine the specific biological activity of PE at a molecular level. METHODS: Fibroblast growth factor (FGF) activity was assessed based on the ability to induce proliferation of FGF receptor (FGFR)-overexpressing BaF3 cells...
October 2, 2017: Journal of Cosmetic Dermatology
https://www.readbyqxmd.com/read/28968756/resistance-mediated-by-alternative-receptor-tyrosine-kinases-in-fgfr1-amplified-lung-cancer
#10
Yuta Adachi, Kazuyoshi Watanabe, Kenji Kita, Hidenori Kitai, Hiroshi Kotani, Yuki Sato, Naohiko Inase, Seiji Yano, Hiromichi Ebi
FGFR1 amplification has been identified in 10%-20% of patients with squamous non-small cell lung cancer. Preclinical models showed promising activity of specific FGFR inhibitors, but early clinical trials showed that only a small fraction of patients with FGFR1-amplified lung cancer responded to FGFR inhibitors. These unsatisfactory results were partly explained by heterogeneous amplicons around the 8p11 genomic region, leading to false positive amplification results. Furthermore, discrepancies in the gene amplification and protein expression of FGFR1 were also reported...
August 31, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28968431/breast-cancer-cell-derived-fibroblast-growth-factors-enhance-osteoclast-activity-and-contribute-to-the-formation-of-metastatic-lesions
#11
Kelly Aukes, Cynthia Forsman, Nicholas J Brady, Kristina Astleford, Nicholas Blixt, Deepali Sachdev, Eric D Jensen, Kim C Mansky, Kathryn L Schwertfeger
Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been implicated in promoting breast cancer growth and progression. While the autocrine effects of FGFR activation in tumor cells have been extensively studied, little is known about the effects of tumor cell-derived FGFs on cells in the microenvironment. Because FGF signaling has been implicated in the regulation of bone formation and osteoclast differentiation, we hypothesized that tumor cell-derived FGFs are capable of modulating osteoclast function and contributing to growth of metastatic lesions in the bone...
2017: PloS One
https://www.readbyqxmd.com/read/28966248/pharmacological-activation-gi-o-protein-increases-glial-cell-line-derived-neurotrophic-factor-production-through-fibroblast-growth-factor-receptor-and-extracellular-signal-regulated-kinase-pathway-in-primary-cultured-rat-cortical-astrocytes
#12
Kazue Hisaoka-Nakashima, Chie Matsumoto, Honami Azuma, Sayaka Taki, Minoru Takebayashi, Yoshihiro Nakata, Norimitsu Morioka
A significant reduction of glial cell line-derived neurotrophic factor (GDNF) has been identified in the pathophysiology of neurodegenerative and neuropsychiatric disorders. Thus, clarification of the mechanism of GDNF production, and modulating brain GDNF levels could be a novel therapeutic approach. A previous study demonstrated that antidepressant amitriptyline-induced GDNF production was significantly inhibited by pertussis toxin (PTX), a Gi/o protein inhibitor in astrocytes, the main source of GDNF in the brain...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28965421/safety-and-efficacy-of-nintedanib-for-the-treatment-of-metastatic-colorectal-cancer
#13
Maria Carmen Riesco-Martinez, Ana Sanchez-Torre, Rocio Garcia-Carbonero
Nintedanib (BIBF 1200) is an oral tyrosine kinase inhibitor that targets the vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR) and fibroblast growth factor (FGFR) receptors. It is approved in Europe in combination with docetaxel for patients with advanced lung adenocarcinoma who have progressed to first-line chemotherapy. However, its role in the treatment of metastatic colorectal cancer (mCRC) is uncertain. Recent results from the LUME-Colon 1 pivotal phase III trial showed only a marginal increase in progression free survival over placebo in refractory mCRC patients, with a toxicity profile similar to other antiangiogenic agents, and no benefit in overall survival...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28965199/fgf-21-plays-a-crucial-role-in-the-glucose-uptake-of-activated-monocytes
#14
Nan Wang, Jun-Yan Li, Ting-Ting Zhao, Si-Ming Li, Cheng-Bin Shen, De-Shan Li, Wen-Fei Wang
Monocytes display a gradual change in metabolism during inflammation. When activated, the increase in glucose utilization is important for monocytes to participate in immune and inflammatory responses. Further studies on the mechanism underlying this biological phenomenon may provide a new understanding of the relationship between immune response and metabolism. The THP-1 cells were used as a monocyte model. The cells were activated with lipopolysaccharide (LPS). Glucose uptake was measured using flow cytometry...
September 30, 2017: Inflammation
https://www.readbyqxmd.com/read/28965185/safety-pharmacokinetic-and-pharmacodynamics-of-erdafitinib-a-pan-fibroblast-growth-factor-receptor-fgfr-tyrosine-kinase-inhibitor-in-patients-with-advanced-or-refractory-solid-tumors
#15
Tomohiro Nishina, Shunji Takahashi, Ryota Iwasawa, Hidehisa Noguchi, Masayuki Aoki, Toshihiko Doi
Introduction This phase 1, open-label, multicenter, single-arm, dose-escalation study aimed to evaluate safety, pharmacokinetics (PK), and pharmacodynamics of erdafitinib (JNJ-42756493), an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, and to determine the recommended phase 2 dose in Japanese patients with advanced or refractory solid tumors. Methods Three to 6 patients were enrolled into sequentially escalating dose cohorts (erdafitinib 2, 4, or 6 mg) with a daily dosing schedule of 21-day cycles or a 7 days-on/7 days-off intermittent schedule (erdafitinib 10 mg or 12 mg) of 28-day cycles...
September 30, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28938491/inhibition-of-fgfr-signaling-partially-rescues-hypophosphatemic-rickets-in-hmwfgf2-tg-male-mice
#16
Liping Xiao, Erxia Du, Collin Homer-Bouthiette, Marja M Hurley
Transgenic mice harboring high molecular weight fibroblast growth factor (FGF)2 isoforms (HMWTg) in osteoblast lineage cells phenocopy human X-linked hypophosphatemic rickets (XLH) and Hyp murine model of XLH demonstrating increased FGF23/FGF receptor signaling and hypophosphatemic rickets. Because HMWFGF2 was upregulated in bones of Hyp mice and abnormal FGF receptor (FGFR) signaling is important in XLH, HMWTg mice were used to examine the effect of the FGFR inhibitor NVP-BGJ398, now in clinical trials for cancer therapy, on hypophosphatemic rickets...
October 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28928360/tumor-associated-b-cells-induce-tumor-heterogeneity-and-therapy-resistance
#17
Rajasekharan Somasundaram, Gao Zhang, Mizuho Fukunaga-Kalabis, Michela Perego, Clemens Krepler, Xiaowei Xu, Christine Wagner, Denitsa Hristova, Jie Zhang, Tian Tian, Zhi Wei, Qin Liu, Kanika Garg, Johannes Griss, Rufus Hards, Margarita Maurer, Christine Hafner, Marius Mayerhöfer, Georgios Karanikas, Ahmad Jalili, Verena Bauer-Pohl, Felix Weihsengruber, Klemens Rappersberger, Josef Koller, Roland Lang, Courtney Hudgens, Guo Chen, Michael Tetzlaff, Lawrence Wu, Dennie Tompers Frederick, Richard A Scolyer, Georgina V Long, Manashree Damle, Courtney Ellingsworth, Leon Grinman, Harry Choi, Brian J Gavin, Margaret Dunagin, Arjun Raj, Nathalie Scholler, Laura Gross, Marilda Beqiri, Keiryn Bennett, Ian Watson, Helmut Schaider, Michael A Davies, Jennifer Wargo, Brian J Czerniecki, Lynn Schuchter, Dorothee Herlyn, Keith Flaherty, Meenhard Herlyn, Stephan N Wagner
In melanoma, therapies with inhibitors to oncogenic BRAF(V600E) are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28927233/fibroblast-growth-factor-2-mediated-fgfr-erk-signaling-supports-maintenance-of-cancer-stem-like-cells-in-esophageal-squamous-cell-carcinoma
#18
Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Shunsuke Ohnishi, Yoshito Komatsu, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Tomoe Shimazaki, Megumi Kimura, Ayaka Asano, Yoshiyuki Fujimoto, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Kelly A Whelan, Hiroshi Nakagawa, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto
In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT)...
September 13, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28915889/anti-fibrotic-efficacy-of-nintedanib-in-pulmonary-fibrosis-via-the-inhibition-of-fibrocyte-activity
#19
Seidai Sato, Shintaro Shinohara, Shinya Hayashi, Shun Morizumi, Shuichi Abe, Hiroyasu Okazaki, Yanjuan Chen, Hisatsugu Goto, Yoshinori Aono, Hirohisa Ogawa, Kazuya Koyama, Haruka Nishimura, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara, Yasuhiko Nishioka
BACKGROUND: Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear...
September 15, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28905937/somcl-085-a-novel-multi-targeted-fgfr-inhibitor-displays-potent-anticancer-activity-in-fgfr-addicted-human-cancer-models
#20
Xi-Fei Jiang, Yang Dai, Xia Peng, Yan-Yan Shen, Yi Su, Man-Man Wei, Wei-Ren Liu, Zhen-Bin Ding, Ao Zhang, Ying-Hong Shi, Jing Ai
Aberrant fibroblast growth factor receptor (FGFR) activation is found across a diverse spectrum of malignancies, especially those lacking effective treatments. SOMCL-085 is a novel FGFR-dominant multi-target kinase inhibitor. Here, we explored the FGFR-targeting anticancer activity of SOMCL-085 both in vitro and in vivo. Among a panel of 20 tyrosine kinases screened, SOMCL-085 potently inhibited FGFR1, FGFR2 and FGFR3 kinase activity, with IC50 values of 1.8, 1.9 and 6.9 nmol/L, respectively. This compound simultaneously inhibited the angiogenesis kinases VEGFR and PDGFR, but without obvious inhibitory effect on other 12 tyrosine kinases...
September 14, 2017: Acta Pharmacologica Sinica
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