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FGFR inhibitors toxicity

Christoph Schliemann, Joachim Gerss, Stefanie Wiebe, Jan-Henrik Mikesch, Nicola Knoblauch, Tim Sauer, Linus Angenendt, Tobias Kewitz, Marc Urban, Trude Butterfass-Bahloul, Sabine Edemir, Kerstin Vehring, Carsten Müller-Tidow, Wolfgang E Berdel, Utz Krug
: Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28-day cycles...
2016: PloS One
Sung Hee Lim, Jong-Mu Sun, Yoon-La Choi, Hye Ryun Kim, Soomin Ahn, Ji Yun Lee, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Joo Hang Kim, Byoung Chul Cho, Myung-Ju Ahn
BACKGROUND: Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driving oncogene in squamous cell cancer (SCC) of the lung. The current phase 2 study evaluated the efficacy and tolerability of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung. METHODS: Patients with pretreated advanced SCC of the lung whose tumors demonstrated FGFR1 amplification of > 5 copies by fluorescence in situ hybridization were enrolled. Dovitinib at a dose of 500 mg was administered orally, once daily, on days 1 to 5 of every week, followed by 2 days off...
October 2016: Cancer
Niklas Schäfer, Gerrit H Gielen, Sied Kebir, Anja Wieland, Andreas Till, Frederic Mack, Christina Schaub, Theophilos Tzaridis, Roman Reinartz, Michael Niessen, Rolf Fimmers, Matthias Simon, Christoph Coch, Christine Fuhrmann, Ulrich Herrlinger, Björn Scheffler, Martin Glas
PURPOSE: Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR β, and c-Kit. Since dovitinib is able to cross the blood-brain barrier and targets brain tumor-relevant pathways, we conducted a phase I trial to demonstrate its safety in recurrent glioblastoma (GBM). PATIENTS AND METHODS: Patients with first or second GBM recurrence started treatment with the maximal tolerated dose (MTD) previously established in systemic cancer patients (500 mg/d, 5 days on/2 days off)...
July 2016: Journal of Cancer Research and Clinical Oncology
Nagaraju Anreddy, Atish Patel, Kamlesh Sodani, Rishil J Kathawala, Eugenie P Chen, John N D Wurpel, Zhe-Sheng Chen
Multidrug resistance protein 7 (MRP7, ABCC10) is a recently identified member of the ATP-binding cassette (ABC) transporter family, which adequately confers resistance to a diverse group of antineoplastic agents, including taxanes, vinca alkaloids and nucleoside analogs among others. Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas (NSCLC) compared to a normal healthy lung tissue. Recent studies revealed increased paclitaxel sensitivity in the Mrp7(-/-) mouse model compared to their wild-type counterparts...
June 2014: Acta Pharmaceutica Sinica. B
Azahara Fernández-Guizán, Alejandro López-Soto, Andrea Acebes-Huerta, Leticia Huergo-Zapico, Mónica Villa-Álvarez, Luz-Elena Núñez, Francisco Morís, Segundo Gonzalez
Demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG-MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA...
2015: PloS One
Iva Gudernova, Iva Vesela, Lukas Balek, Marcela Buchtova, Hana Dosedelova, Michaela Kunova, Jakub Pivnicka, Iva Jelinkova, Lucie Roubalova, Alois Kozubik, Pavel Krejci
Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation...
January 1, 2016: Human Molecular Genetics
Jih-Ing Chuang, Jui-Yen Huang, Shaw-Jenq Tsai, H Sunny Sun, Shang-Hsun Yang, Pei-Chin Chuang, Bu-Miin Huang, Cheng-Hsin Ching
Our previous studies demonstrated that fibroblast growth factor 9 (FGF9) protects cortical and dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative insult by upregulation of γ-glutamylcysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1). However, the mechanisms responsible for FGF9-induced γ-GCS and HO-1 upregulation remain uncharacterized. In the present study, we demonstrate the signaling pathways by which FGF9 upregulates HO-1 and γ-GCS expression. We found that FGF9-induced HO-1 and γ-GCS expression was prevented by PD173014, an inhibitor of the FGF receptor (FGFR)...
December 2015: Free Radical Biology & Medicine
Josep Tabernero, Rastislav Bahleda, Rodrigo Dienstmann, Jeffrey R Infante, Alain Mita, Antoine Italiano, Emiliano Calvo, Victor Moreno, Barbara Adamo, Anas Gazzah, Bob Zhong, Suso J Platero, Johan W Smit, Kim Stuyckens, Moitreyee Chatterjee-Kishore, Jordi Rodon, Vijay Peddareddigari, Feng R Luo, Jean-Charles Soria
PURPOSE: JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493. PATIENTS AND METHODS: Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.5 to 12 mg administered continuously daily or JNJ-42756493 10 or 12 mg administered intermittently (7 days on/7 days off)...
October 20, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Mehdi Touat, Ecaterina Ileana, Sophie Postel-Vinay, Fabrice André, Jean-Charles Soria
The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies...
June 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sun Min Lim, Woong Youn Chung, Kee-Hyun Nam, Sang-Wook Kang, Jae Yun Lim, Hoon-Gu Kim, Seong Hoon Shin, Jong-Mu Sun, Seong-Geun Kim, Joo-Hang Kim, Chan Woo Kang, Hye Ryun Kim, Byoung Chul Cho
BACKGROUND: This phase 2 study investigated the efficacy and safety of dovitinib (TKI258), a receptor tyrosine kinase inhibitor with potent activity against fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR), in locally advanced or metastatic thyroid cancer patients. PATIENTS AND METHODS: Patients with advanced thyroid cancer that was refractory or not appropriate for (131)I received dovitinib orally, 500mg once daily for five consecutive days, followed by a 2-day rest every week...
August 2015: European Journal of Cancer
Don S Dizon, Michael W Sill, Jeanne M Schilder, Kathryn F McGonigle, Zia Rahman, David S Miller, David G Mutch, Kimberly K Leslie
INTRODUCTION: Patients presenting with advanced, recurrent, or metastatic endometrial cancer have limited treatment options. On behalf of the Gynecologic Oncology Group, we conducted this phase II trial of nintedanib (BIBF 1120), a potent small molecule triple receptor tyrosine kinase inhibitor of PDGFR α and β, FGFR 1/3, and VEGFR 1-3, in this population. OBJECTIVES: The primary objectives were to estimate event-free survival (EFS) at 6 months and the proportion of patients who have an objective tumor response...
December 2014: Gynecologic Oncology
J-C Soria, F DeBraud, R Bahleda, B Adamo, F Andre, R Dienstmann, R Dientsmann, A Delmonte, R Cereda, J Isaacson, J Litten, A Allen, F Dubois, C Saba, R Robert, M D'Incalci, M Zucchetti, M G Camboni, J Tabernero
BACKGROUND: Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and β (PGFRα/β), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors...
November 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Lucie Peuvrel, Brigitte Dréno
Targeted therapies have developed rapidly over the last few years in the field of oncology thanks to a better understanding of carcinogenesis. They target pathways involved in signal transduction (EGFR, HER2, HER3, HER4, FLT3, RAS, RAF, MEK, KIT, RET, mTOR, SRC, EPH, SCF), tumor angiogenesis (VEGFR, TIE2), and tumor microenvironment (PDGFR, FGFR). They rarely cause the systemic adverse reactions generally associated with chemotherapy, but frequently cause disabling and specific skin toxicity. The impact on patient quality of life can be important both in terms of symptoms caused and of potentially aesthetic consequences...
October 2014: American Journal of Clinical Dermatology
Matthew A Powell, Michael W Sill, Paul J Goodfellow, Doris M Benbrook, Heather A Lankes, Kimberly K Leslie, Yvette Jeske, Robert S Mannel, Monique A Spillman, Paula S Lee, James S Hoffman, D Scott McMeekin, Pamela M Pollock
PURPOSE: Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS: Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2...
October 2014: Gynecologic Oncology
Emma Di Carlo, Carlo Sorrentino, Alessia Zorzoli, Serena Di Meo, Maria Grazia Tupone, Emanuela Ognio, Gabriella Mincione, Irma Airoldi
Prostate cancer (PCa) is of increasing significance worldwide as a consequence of the population ageing. Fragile elderly patients may particularly benefit from noninvasive and well tolerable immunotherapeutic approaches. Preclinical studies have revealed that the immune-regulatory cytokine IL-27 may exert anti-tumor activities in a variety of tumor types without discernable toxicity. We, thus, investigated whether IL-27 may function as anti-tumor agent in human (h) PCa and analyzed the rationale for its clinical application...
November 15, 2014: Oncotarget
R Dienstmann, J Rodon, A Prat, J Perez-Garcia, B Adamo, E Felip, J Cortes, A J Iafrate, P Nuciforo, J Tabernero
The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro and in vivo tumor models harboring FGFR aberrations, a growing number of research groups have selected FGFRs as targets for anticancer drug development. Multikinase FGFR/vascular endothelial growth factor receptor (VEGFR) inhibitors have shown promising activity in breast cancer patients with FGFR1 and/or FGF3 amplification...
March 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Han Kiat Ho, Angie Hui Ling Yeo, Tse Siang Kang, Boon Tin Chua
Aberrations in fibroblast growth factor receptor (FGFR) signaling are instrumental to the pathophysiology of several malignancies and disorders. Hence, FGFR inhibitors are explored in therapeutics with early candidates developed as competitors for the ATP-binding pocket in the kinase domain. More recent programs yielded compounds of diverse scaffolds with alternative binding modes. Concurrently, monoclonal antibodies and peptide-based agents provide independent options for clinical development. Notwithstanding this rapid progress, we contemplate the toxicological impact of FGFR inhibition based on the defined role of FGFR family members in physiology and homeostasis...
January 2014: Drug Discovery Today
Christian Rolfo, Luis E Raez, Giuseppe Bronte, Edgardo S Santos, Kostantinos Papadimitriou, Lucio Buffoni, Jan P van Meerbeeck, Antonio Russo
INTRODUCTION: Several new targeted agents with anti-angiogenic properties have been developed recently, including vandetanib, sunitinib, sorafenib, bevacizumab and others. Tumor development, progression, metastasis are strongly linked to angiogenesis. Targeted agents like bevacizumab, a monoclonal antibody which targets VEGF, have been fully developed in several solid tumors. These new agents strongly advocate that targeting angiogenesis is one of the best approaches for cancer therapy...
August 2013: Expert Opinion on Investigational Drugs
Angiolo Gadducci, Claudia Sergiampietri, Ilaria Guiggi
The limited efficacy of endocrine therapy and chemotherapy has stimulated several researches aimed to detect novel molecularly target therapies for advanced, persistent or recurrent endometrial cancer. Prior attempts to block vascular endothelial growth factor (VEGF) with sunitinib, sorafenib and thalidomide have obtained disappointing results. Bevacizumab has shown a promising activity in a phase II study. The percentages of patients with progression-free survival ≥6 months were similar for endometrioid (35%) and serous carcinoma (36%), but the number of cases was too small to assess the relevance of histological type for response to bevacizumab...
September 2013: Gynecological Endocrinology
Viktor Grünwald, Axel Stuart Merseburger
The field of renal cell carcinoma (RCC) treatment has changed dramatically during recent years. Sunitinib, sorafenib and pazopanib were the first generation of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) to have significant clinical activity in metastatic clear cell RCC. These TKI share inhibition of VEGFR family members, but differ in their ability to block other cellular kinases. Axitinib and tivozanib are 2nd generation TKIs, which show high specificity for VEGFR inhibition and exert a favourable toxicity profile...
July 2013: European Journal of Cancer
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