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https://www.readbyqxmd.com/read/28736639/promising-therapeutics-of-gastrointestinal-cancers-in-clinical-trials
#1
REVIEW
Lingling Du, Zheng Che, Andrea Wang-Gillam
Many novel therapeutics are being developed for patients with cancers along the gastrointestinal (GI) tract. These emerging agents are frequently classified by their biological targets such as tumor growth pathways, tumor metabolism, microenvironment, etc. Some agents targeting cancer growth pathways are based on existing clinically validated therapeutic targets, such as regorafenib for hepatocellular carcinoma (HCC), while other agents focus on newly identified targets, such as FGFR fusions in cholangiocarcinoma...
June 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28728751/a-phase-ii-evaluation-of-brivanib-in-the-treatment-of-persistent-or-recurrent-carcinoma-of-the-cervix-an-nrg-oncology-gynecologic-oncology-group-study
#2
John K Chan, Wei Deng, Robert V Higgins, Krishnansu S Tewari, Albert J Bonebrake, Michael Hicks, Stephanie Gaillard, Pedro T Ramirez, Weldon Chafe, Bradley J Monk, Carol Aghajanian
BACKGROUND: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. METHODS: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity...
July 17, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28721753/nintedanib-in-ovarian-cancer
#3
Saira Khalique, Susana Banerjee
Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR α and β, which has entered phase III trial development in ovarian cancer. Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far...
July 19, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28714692/design-synthesis-and-pharmacological-evaluation-of-novel-multisubstituted-pyridin-3-amine-derivatives-as-multitargeted-protein-kinase-inhibitors-for-the-treatment-of-non-small-cell-lung-cancer
#4
Wei Zhu, Hui Chen, Yulan Wang, Jiang Wang, Xia Peng, Xianjie Chen, Yinglei Gao, Chunpu Li, Yulong He, Jing Ai, Meiyu Geng, Mingyue Zheng, Hong Liu
A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast growth factor receptors (FGFR), which was subsequently validated by in vitro experiments. The structure-activity relationship (SAR) of its analogues was then explored to afford novel FGFR inhibitors 2a-2p and 3a-3q. Among them, 3m showed potent inhibition against FGFR1, 2, and 3...
July 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28714017/targeting-vegfr-and-fgfr-in-head-and-neck-squamous-cell-carcinoma-in-vitro
#5
Roman C Brands, Luise M Knierim, Francesco De Donno, Valentin Steinacker, Stefan Hartmann, Axel Seher, Alexander C Kübler, Urs D A Müller-Richter
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by a tumor microenvironment (TME) that overexpresses vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which can lead to neovascularization, tumor growth and metastasis. Therapeutic strategies inhibiting these signaling pathways might lead to innovative HNSCC treatments. Five HNSCC cell lines were characterized based on VEGFR1-3 and FGFR1-4 expression by sqRT-PCR and treated with three different tyrosine kinase inhibitors (TKIs) (nintedanib, dovitinib and pazopanib), all of which are effective against VEGFR and FGFR family members...
July 10, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28707601/potential-role-of-natural-compounds-as-anti-angiogenic-agents-in-cancer
#6
Muthu K Shanmugam, Sudha Warrier, Alan Prem Kumar, Gautam Sethi, Frank Arfuso
BACKGROUND: Neovascularization, also known as angiogenesis, is the process of capillary sprouting from pre-existing blood vessels. This physiological process is a hallmark event in normal embryonic development as blood vessels generally supply both oxygen and nutrients to the cells of the body. Any disruption in this process can lead to the development of various chronic diseases, including cancer. In cancer, aberrant angiogenesis plays a prominent role in maintaining sustained tumor growth to malignant phenotypes and promoting metastasis...
July 12, 2017: Current Vascular Pharmacology
https://www.readbyqxmd.com/read/28687204/optimization-of-1h-indazol-3-amine-derivatives-as-potent-fibroblast-growth-factor-receptor-inhibitors
#7
Jing Cui, Xia Peng, Dingding Gao, Yang Dai, Jing Ai, Yingxia Li
Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy because of its critical role in promoting cancer formation and progression. In a continuing effort to improve the cellular activity of hit compound 7r bearing an indazole scaffold, which was previously discovered by our group, several compounds harnessing fluorine substituents were designed, synthesized and biological evaluated. Besides, the region extended out to the ATP binding pocket toward solvent was also explored. Among them, compound 2a containing 2,6-difluoro-3-methoxyphenyl residue exhibited the most potent activities (FGFR1: less than 4...
June 27, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28685321/targeting-fgfr-in-squamous-cell-carcinoma-of-the-lung
#8
Neda Hashemi-Sadraei, Nasser Hanna
Unlike for adenocarcinomas of the lung, no molecular targeted therapies have yet been developed for squamous cell lung cancers, because targetable oncogenic aberrations are scarce in this tumor type. Recent discoveries have established that the fibroblast growth factor (FGF) signaling pathway plays a fundamental role in cancer development by supporting tumor angiogenesis and cancer cell proliferation via different mechanisms. Through comprehensive genomic studies, aberrations in the FGF pathway have been identified in various tumor types, including squamous cell lung cancer, making FGF receptor (FGFR) a potentially druggable target in this malignancy...
July 6, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28676423/functional-interplay-between-secreted-ligands-and-receptors-in-melanoma
#9
REVIEW
Cecilia Herraiz, Celia Jiménez-Cervantes, Berta Sánchez-Laorden, José C García-Borrón
Melanoma, the most aggressive form of skin cancer, results from the malignant transformation of melanocytes located in the basement membrane separating the epidermal and dermal skin compartments. Cutaneous melanoma is often initiated by solar ultraviolet radiation (UVR)-induced mutations. Melanocytes intimately interact with keratinocytes, which provide growth factors and melanocortin peptides acting as paracrine regulators of proliferation and differentiation. Keratinocyte-derived melanocortins activate melanocortin-1 receptor (MC1R) to protect melanocytes from the carcinogenic effect of UVR...
July 1, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/28667006/whole-genome-and-epigenomic-landscapes-of-etiologically-distinct-subtypes-of-cholangiocarcinoma
#10
Apinya Jusakul, Ioana Cutcutache, Chern Han Yong, Jing Quan Lim, Mi Ni Huang, Nisha Padmanabhan, Vishwa Nellore, Sarinya Kongpetch, Alvin Wei Tian Ng, Ley Moy Ng, Su Pin Choo, Swe Swe Myint, Raynoo Thanan, Sanjanaa Nagarajan, Weng Khong Lim, Cedric Chuan Young Ng, Arnoud Boot, Mo Liu, Choon Kiat Ong, Vikneswari Rajasegaran, Stefanus Lie, Alvin Soon Tiong Lim, Tse Hui Lim, Jing Tan, Jia Liang Loh, John R McPherson, Narong Khuntikeo, Vajaraphongsa Bhudhisawasdi, Puangrat Yongvanit, Sopit Wongkham, Yasushi Totoki, Hiromi Nakamura, Yasuhito Arai, Satoshi Yamasaki, Pierce K H Chow, Alexander Yaw Fui Chung, London Lucien Peng Jin Ooi, Kiat Hon Lim, Simona Dima, Dan G Duda, Irinel Popescu, Philippe Broet, Sen-Yung Hsieh, Ming-Chin Yu, Aldo Scarpa, Jiaming Lai, Di-Xian Luo, Andre Lopes Carvalho, André Luiz Vettore, Hyungjin Rhee, Young Nyun Park, Ludmil Alexandrov, Raluca Gordan, Steven G Rozen, Tatsuhiro Shibata, Chawalit Pairojkul, Bin Tean Teh, Patrick Tan
Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analysed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined four CCA clusters - Fluke-Positive CCAs (Clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations, conversely Fluke-Negative CCAs (Clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements...
June 30, 2017: Cancer Discovery
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
#11
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...
July 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28650667/gender-specific-association-between-fgfr4-gly388arg-gene-variants-and-hypertension
#12
Nasser M Al-Daghri, Abdul Khader Mohammed, Omar S Al-Attas, Hossam M Draz, Majed S Alokail
AIMS: Variations in fibroblast growth factor (FGF) levels have been associated with alterations in blood pressure. FGFs mediate their function through binding to their FGF receptor (FGFR). The FGFR4 Gly388Arg polymorphism is associated with cancer and cardiovascular diseases, but its association with hypertension is unclear. Here, we aimed to investigate the association between the FGFR4 Gly388Arg polymorphism and hypertension. MATERIALS AND METHODS: Three hundred Saudi individuals (150 normotensive controls and 150 hypertensive subjects) were genotyped for the FGFR4 Gly388Arg (G/A) polymorphism using polymerase chain reaction-restriction fragment length polymorphism method...
July 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28649871/the-potential-role-of-nintedanib-in-treating-colorectal-cancer
#13
Antonio Rossi, Tiziana Pia Latiano, Paola Parente, Cinzia Chiarazzo, Filomena Limosani, Gabriele Di Maggio, Evaristo Maiello
Angiogenesis leads to the growth, progression, and metastases of a variety of solid tumors, including metastatic colorectal cancer (mCRC), involving particularly the family of vascular endothelial growth factors (VEGF) and their receptors (VEGFR). Several anti-angiogenic inhibitors are already registered for mCRC therapy: bevacizumab, aflibercept, ramucirumab, regorafenib. Nintedanib is a new triple angiokinase oral inhibitor that potently blocks the proangiogenic pathways mediated by VEGFR, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR)...
August 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28630215/mechanisms-of-primary-drug-resistance-in-fgfr1-amplified-lung-cancer
#14
Florian Malchers, Meryem Seda Ercanoglu, Daniel Schütte, Roberta Castiglione, Verena Tischler, Sebastian Michels, Ilona Dahmen, Johannes Brägelmann, Roopika Menon, Johannes M Heuckmann, Julie George, Sascha Ansén, Martin L Sos, Alex Soltermann, Martin Peifer, Jurgen Wolf, Reinhard Büttner, Roman K Thomas
<br />The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells...
June 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28624695/first-in-human-phase-i-study-of-oral-s49076-a-unique-met-axl-fgfr-inhibitor-in-advanced-solid-tumours
#15
Jordi Rodon, Sophie Postel-Vinay, Antoine Hollebecque, Paolo Nuciforo, Analia Azaro, Valérie Cattan, Lucie Marfai, Isabelle Sudey, Karl Brendel, Audrey Delmas, Stéphanie Malasse, Jean-Charles Soria
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD...
August 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28619752/the-met-axl-fgfr-inhibitor-s49076-impairs-aurora-b-activity-and-improves-the-antitumor-efficacy-of-radiotherapy
#16
Céline Clémenson, Cyrus Chargari, Winchygn Liu, Michele Mondini, Charles Ferté, Mike F Burbridge, Valérie Cattan, Anne Jacquet-Bescond, Eric Deutsch
Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefinitib in NSCLC patients whose tumors show resistance to EGFR inhibitors...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28615371/a-phase-1b-open-label-multicentre-study-of-azd4547-in-patients-with-advanced-squamous-cell-lung-cancers
#17
Paul K Paik, Ronglai Shen, Michael F Berger, David Ferry, Jean-Charles Soria, Alastair Mathewson, Claire Rooney, Neil R Smith, Marie Cullberg, Elaine Kilgour, Donal Landers, Paul Frewer, A Nigel Brooks, Fabrice André
Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in ~20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with anti-tumor activity in FGFR1 amplified SQCLC cell lines and patient-derived xenografts. <br /><br />Experimental Design: Based on these data, we performed a phase 1 study of AZD4547 in patients with previously treated stage IV FGFR1 amplified SQCLCs (NCT00979134)...
June 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28611104/cisplatin-increases-sensitivity-to-fgfr-inhibition-in-patient-derived-xenograft-models-of-lung-squamous-cell-carcinoma
#18
Clare E Weeden, Aliaksei Z Holik, Richard J Young, Stephen B Ma, Jean-Marc Garnier, Stephen B Fox, Phillip Antippa, Louis B Irving, Daniel P Steinfort, Gavin M Wright, Prudence A Russell, Matthew E Ritchie, Christopher J Burns, Benjamin Solomon, Marie-Liesse Asselin-Labat
Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including amplification of the fibroblast growth factor receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 amplification as a biomarker of response, or the need for combination treatment...
June 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28598150/high-yield-site-specific-conjugation-of-fibroblast-growth-factor-1-with-monomethylauristatin-e-via-cysteine-flanked-by-basic-residues
#19
Michal Lobocki, Malgorzata Zakrzewska, Anna Szlachcic, Mateusz A Krzyscik, Aleksandra Sokolowska-Wedzina, Jacek Otlewski
Site-specific conjugation is a leading trend in the development of protein conjugates, including antibody-drug conjugates (ADCs), suitable for targeted cancer therapy. Here, we present a very efficient strategy for specific attachment of a cytotoxic drug to fibroblast growth factor 1 (FGF1), a natural ligand of FGF receptors (FGFRs), which are over-expressed in several types of lung, breast, and gastric cancers and are therefore an attractive molecular target. Recently, we showed that FGF1 fused to monomethylauristatin E (vcMMAE) was highly cytotoxic to cells presenting FGFRs on their surface and could be used as a targeting agent alternative to an antibody...
June 23, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28589492/a-phase-1-study-of-ly2874455-an-oral-selective-pan-fgfr-inhibitor-in-patients-with-advanced-cancer
#20
Michael Michael, Yung-Jue Bang, Young Suk Park, Yoon-Koo Kang, Tae Min Kim, Oday Hamid, Donald Thornton, Sonya C Tate, Eyas Raddad, Jeanne Tie
BACKGROUND: We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor. OBJECTIVE: The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455. PATIENTS AND METHODS: This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC)...
August 2017: Targeted Oncology
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