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https://www.readbyqxmd.com/read/28342996/induction-of-neuroendocrine-differentiation-in-prostate-cancer-cells-by-dovitinib-tki-258-and-its-therapeutic-implications
#1
Shalini S Yadav, Jinyi Li, Jennifer A Stockert, Bryan Herzog, James O'Connor, Luis Garzon-Manco, Ramon Parsons, Ashutosh K Tewari, Kamlesh K Yadav
Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT); however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC). With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC...
March 24, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28341788/discovery-and-pharmacological-characterization-of-jnj-42756493-erdafitinib-a-functionally-selective-small-molecule-fgfr-family-inhibitor
#2
Timothy P S Perera, Eleonora Jovcheva, Laurence Mevellec, Jorge Vialard, Desiree De Lange, Tinne Verhulst, Caroline Paulussen, Kelly Van De Ven, Peter King, Eddy Freyne, David C Rees, Matthew Squires, Gordon Saxty, Martin Page, Ron Gilissen, Christopher W Murray, George Ward, Neil T Thompson, David R Newell, Na Cheng, Liang Xie, Jennifer Yang, Suso J Platero, Jayaprakash D Karkera, Christopher Moy, Patrick Angibaud, Sylvie Laquerre, Matthew V Lorenzi
Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases...
March 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28340475/irinotecan-upregulates-fibroblast-growth-factor-receptor-3-expression-in-colorectal-cancer-cells-which-mitigates-irinotecan-induced-apoptosis
#3
Zeynep N Erdem, Stefanie Schwarz, Daniel Drev, Christine Heinzle, Andrea Reti, Petra Heffeter, Xenia Hudec, Klaus Holzmann, Bettina Grasl-Kraupp, Walter Berger, Michael Grusch, Brigitte Marian
BACKGROUND: Irinotecan (IRI) is an integral part of colorectal cancer (CRC) therapy, but response rates are unsatisfactory and resistance mechanisms are still insufficiently understood. As fibroblast growth factor receptor 3 (FGFR3) mediates essential survival signals in CRC, it is a candidate gene for causing intrinsic resistance to IRI. METHODS: We have used cell line models overexpressing FGFR3 to study the receptor's impact on IRI response. For pathway blockade, a dominant-negative receptor mutant and a small molecule kinase inhibitor were employed...
March 21, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28327938/targeting-the-fibroblast-growth-factor-receptor-2-in-gastric-cancer-promise-or-pitfall
#4
C Hierro, M Alsina, M Sánchez, V Serra, J Rodon, J Tabernero
Gastric cancer is the third leading cause of death from cancer worldwide. Systemic chemotherapy remains the mainstay therapeutic option for this poor prognosis cancer. Trastuzumab, the epidermal growth factor receptor 2 (ERBB2 or HER2)-antibody, is the only biological agent approved for the molecularly-selected population of HER2-positive gastric cancer patients. Over the last decade, several groups have been working for deepening into the molecular characterization of gastric cancer, shedding some light into the heterogeneity of this tumour...
March 7, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28314589/fgfr2-mutations-are-associated-with-poor-outcomes-in-endometrioid-endometrial-cancer-an-nrg-oncology-gynecologic-oncology-group-study
#5
Yvette W Jeske, Shamshad Ali, Sara A Byron, Feng Gao, Robert S Mannel, Rahel G Ghebre, Paul A DiSilvestro, Shashikant B Lele, Michael L Pearl, Amy P Schmidt, Heather A Lankes, Nilsa C Ramirez, Golnar Rasty, Matthew Powell, Paul J Goodfellow, Pamela M Pollock
PURPOSE: Activating FGFR2 mutations have been identified in ~10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. METHODS: Tumors were collected as part of the GOG 210 clinical trial "Molecular Staging of Endometrial Cancer" where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up...
March 14, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28264865/gatekeeper-mutations-and-intratumoral-heterogeneity-in-fgfr2-translocated-cholangiocarcinoma
#6
Elizabeth C Smyth, Irina S Babina, Nicholas C Turner
FGFR2 genetic translocations are frequent in cholangiocarcinoma, yet despite initial sensitivity to FGFR inhibitors in clinic, patients quickly become resistant to targeted therapies. The work published by Goyal and colleagues demonstrates that acquisition of gatekeeper mutations in FGFR2 and intratumoral heterogeneity drive resistance in patients with FGFR2-translocated intrahepatic cholangiocarcinoma, which will have important implications for management of the disease in clinic. Cancer Discov; 7(3); 248-9...
March 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28263980/an-fgfr-inhibitor-converts-the-tumor-promoting-effect-of-tgf-%C3%AE-by-the-induction-of-fibroblast-associated-genes-of-hepatoma-cells
#7
H-R Zhang, X-D Wang, X Yang, D Chen, J Hao, R Cao, X-Z Wu
Tumors consistently mimic wound-generating chronic inflammation; however, why they do not heal like wounds with fibrotic scars remains unknown. The components of the tumor microenvironment, such as transforming growth factor β (TGF-β) and fibroblast growth factors (FGFs), may account for this phenomenon. Tumor formation involves continuous activation of the FGF pathway, whereas the repair of tissue injury is a self-limiting process accompanied with controlled activation of the FGF pathway. In the tumor microenvironment TGF-β increases the secretion of FGFs, further promoting the malignant biological properties of tumors...
March 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28255027/akt-activation-mediates-acquired-resistance-to-fibroblast-growth-factor-receptor-inhibitor-bgj398
#8
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...
March 2, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28240679/in-vitro-and-in-vivo-combined-effect-of-arq-092-an-akt-inhibitor-with-arq-087-a-fgfr-inhibitor
#9
Yi Yu, Terence Hall, Sudharshan Eathiraj, Michael J Wick, Brian Schwartz, Giovanni Abbadessa
The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the drug development efforts targeting this pathway with therapeutic interventions have been advanced by academic and industrial groups. However, the clinical outcome is moderate. Combination of inhibition of PI3K/AKT and other targeted agents became a feasible approach. In this study we assessed the combined effect of ARQ 092, a pan-AKT inhibitor, and ARQ 087, a pan-FGFR inhibitor, in vitro and in vivo. In a panel of 45 cancer cell lines, on 24% (11 out of 45) the compounds showed synergistic effect, on 62% (28 out of 45) additive, and on 13% (6 out of 45) antagonistic...
February 24, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28212293/targeting-angiogenesis-in-biliary-tract-cancers-an-open-option
#10
REVIEW
Valeria Simone, Oronzo Brunetti, Luigi Lupo, Mario Testini, Eugenio Maiorano, Michele Simone, Vito Longo, Christian Rolfo, Marc Peeters, Aldo Scarpa, Amalia Azzariti, Antonio Russo, Domenico Ribatti, Nicola Silvestris
Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer...
February 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28183331/phase-ii-randomized-placebo-controlled-study-of-dovitinib-in-combination-with-fulvestrant-in-postmenopausal-patients-with-hr-her2-breast-cancer-that-had-progressed-during-or-after-prior-endocrine-therapy
#11
Antonino Musolino, Mario Campone, Patrick Neven, Neelima Denduluri, Carlos H Barrios, Javier Cortes, Kimberly Blackwell, Hatem Soliman, Zsuzsanna Kahan, Hervé Bonnefoi, Matthew Squires, Yong Zhang, Stephanie Deudon, Michael M Shi, Fabrice André
BACKGROUND: Overexpression of fibroblast growth factor receptor 1 (FGFR1), found in ≤8% of hormone receptor-positive (HR(+)), human epidermal growth factor receptor 2-negative (HER2(-)) breast cancer cases, is correlated with decreased overall survival and resistance to endocrine therapy (ET). Dovitinib, a potent FGFR inhibitor, has demonstrated antitumor activity in heavily pretreated patients with FGFR pathway-amplified breast cancer. METHODS: In this randomized, placebo-controlled phase II trial, we evaluated whether the addition of dovitinib to fulvestrant would improve outcomes in postmenopausal patients with HR(+), HER2(-) advanced breast cancer that had progressed during or after prior ET...
February 10, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28161661/multi-chemotherapeutic-schedules-containing-the-pan-fgfr-inhibitor-arq-087-are-safe-and-show-antitumor-activity-in-different-xenograft-models
#12
Rosaria Chilà, Terence Hall G, Giovanni Abbadessa, Massimo Broggini, Giovanna Damia
ARQ 087 is a multi-tyrosine kinase inhibitor with potent activity against the FGFR receptor family, currently in Phase I clinical studies for the treatment of advanced solid tumors. The compound has a very safe profile and induces tumor regressions in FGFR-driven models. The feasibility of combining ARQ 087 with chemotherapy was investigated in FGFR deregulated human xenografts. Nude mice were transplanted subcutaneously with H1581, and when tumor masses reached 150 mg, were randomized to receive vehicle, ARQ 087, paclitaxel, carboplatin as single agents or in combination...
February 2, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28124835/a-pareto-algorithm-for-efficient-de-novo-design-of-multi-functional-molecules
#13
Frits Daeyaert, Micheal W Deem
We have introduced a Pareto sorting algorithm into Synopsis, a de novo design program that generates synthesizable molecules with desirable properties. We give a detailed description of the algorithm and illustrate its working in 2 different de novo design settings: the design of putative dual and selective FGFR and VEGFR inhibitors, and the successful design of organic structure determining agents (OSDAs) for the synthesis of zeolites. We show that the introduction of Pareto sorting not only enables the simultaneous optimization of multiple properties but also greatly improves the performance of the algorithm to generate molecules with hard-to-meet constraints...
January 2017: Molecular Informatics
https://www.readbyqxmd.com/read/28122360/acquired-resistance-to-ly2874455-in-fgfr2-amplified-gastric-cancer-through-an-emergence-of-novel-fgfr2-acsl5-fusion
#14
Sun Young Kim, Taejin Ahn, Heejin Bang, Jun Soo Ham, Jusun Kim, Seung Tae Kim, Jiryeon Jang, Moonhee Shim, So Young Kang, Se Hoon Park, Byung Hoon Min, Hyuk Lee, Won Ki Kang, Kyoung-Mee Kim, Woongyang Park, Jeeyun Lee
BACKGROUND: Fibroblast growth factor 2 (FGFR2) amplification, occurring in ~2-9% of gastric cancers (GC), is associated with poor overall survival. RESULTS: RNA sequencing identified a novel FGFR2-ACSL5 fusion in the resistant tumor that was absent from the matched pre-treatment tumor. The FGFR2-amplified PDC line was sensitive to FGFR inhibitors whereas the PDC line with concomitant FGFR2 amplification and FGFR2-ACSL5 fusion exhibited resistance. Additionally, the FGFR2-amplified GC PDC line, which was initially sensitive to FGFR2 inhibitors, subsequently also developed resistance...
January 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28121208/fgfr-targeted-therapeutics-for-the-treatment-of-breast-cancer
#15
REVIEW
Antonella De Luca, Daniela Frezzetti, Marianna Gallo, Nicola Normanno
Breast cancer is a complex disease and several molecular drivers regulate its progression. Fibroblast growth factor receptor (FGFR) signaling is frequently deregulated in many cancers, including breast cancer. Due the involvement of the FGFR/FGF axis in the pathogenesis and progression of tumors, FGFR-targeted agents might represent a potential therapeutic option for breast cancer patients. Areas covered: This review offers an overview of targeted agents against FGFRs and their clinical development in breast cancer...
March 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28119489/pi3k-inhibitors-synergize-with-fgfr-inhibitors-to-enhance-antitumor-responses-in-fgfr2-mutant-endometrial-cancers
#16
Leisl Packer, Xinyan Geng, Vanessa F Bonazzi, Robert Ju, Clare Mahon, Margaret C Cummings, Sally-Anne Stephenson, Pamela M Pollock
Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer (EC). ECs display hyper-activation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA and PIK3R1. FGFR2, as well as the PI3K pathway, have emerged as potential therapeutic targets in EC. Activation of the PI3K pathway is seen in >90% of FGFR2mutant ECs. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719...
January 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28117910/oligodendroglial-fibroblast-growth-factor-receptor-1-gene-targeting-protects-mice-from-experimental-autoimmune-encephalomyelitis-through-erk-akt-phosphorylation
#17
Ranjithkumar Rajendran, Mario Giraldo Velásquez, Christine Stadelmann, Martin Berghoff
Fibroblast growth factors (FGFs) exert diverse biological effects by binding and activation of specific fibroblast growth factor receptors (FGFRs). FGFs and FGFRs have been implicated in demyelinating pathologies including multiple sclerosis. In vitro activation of the FGF2/FGFR1 pathway results in downregulation of myelin proteins. FGF1, 2 and 9 have been shown to be involved in the pathology of multiple sclerosis. Recent studies on the function of oligodendroglial FGFR1 in a model of toxic demyelination showed that deletion of FGFR1 led to increased remyelination and preservation of axonal density and an increased number of mature oligodendrocytes...
January 24, 2017: Brain Pathology
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
#18
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)...
January 17, 2017: European Urology
https://www.readbyqxmd.com/read/28094372/theoretical-studies-on-fgfr-isoform-selectivity-of-fgfr1-fgfr4-inhibitors-by-molecular-dynamics-simulations-and-free-energy-calculations
#19
Weitao Fu, Lingfeng Chen, Zhe Wang, Yanting Kang, Chao Wu, Qinqin Xia, Zhiguo Liu, Jianmin Zhou, Guang Liang, Yuepiao Cai
The activation and overexpression of fibroblast growth factor receptors (FGFRs) are highly correlated with a variety of cancers. Most small molecule inhibitors of FGFRs selectively target FGFR1-3, but not FGFR4. Hence, designing highly selective inhibitors towards FGFR4 remains a great challenge because FGFR4 and FGFR1 have a high sequence identity. Recently, two small molecule inhibitors of FGFRs, ponatinib and AZD4547, have attracted huge attention. Ponatinib, a type II inhibitor, has high affinity towards FGFR1/4 isoforms, but AZD4547, a type I inhibitor of FGFR1, displays much reduced inhibition toward FGFR4...
February 1, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28092370/api5-confers-cancer-stem-cell-like-properties-through-the-fgf2-nanog-axis
#20
K-H Song, H Cho, S Kim, H-J Lee, S J Oh, S R Woo, S-O Hong, H S Jang, K H Noh, C H Choi, J-Y Chung, S M Hewitt, J-H Kim, M Son, S-H Kim, B I Lee, H-C Park, Y-K Bae, T W Kim
Immune selection drives the evolution of tumor cells toward an immune-resistant and cancer stem cell (CSC)-like phenotype. We reported that apoptosis inhibitor-5 (API5) acts as an immune escape factor, which has a significant role in controlling immune resistance to antigen-specific T cells, but its functional association with CSC-like properties remains largely unknown. In this study, we demonstrated for the first time that API5 confers CSC-like properties, including NANOG expression, the frequency of CD44-positive cells and sphere-forming capacity...
January 16, 2017: Oncogenesis
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