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https://www.readbyqxmd.com/read/28447912/targeting-ret-in-patients-with-ret-rearranged-lung-cancers-results-from-the-global-multicenter-ret-registry
#1
Oliver Gautschi, Julie Milia, Thomas Filleron, Juergen Wolf, David P Carbone, Dwight Owen, Ross Camidge, Vignhesh Narayanan, Robert C Doebele, Benjamin Besse, Jordi Remon-Masip, Pasi A Janne, Mark M Awad, Nir Peled, Chul-Cho Byoung, Daniel D Karp, Michael Van Den Heuvel, Heather A Wakelee, Joel W Neal, Tony S K Mok, James C H Yang, Sai-Hong Ignatius Ou, Georg Pall, Patrizia Froesch, Gérard Zalcman, David R Gandara, Jonathan W Riess, Vamsidhar Velcheti, Kristin Zeidler, Joachim Diebold, Martin Früh, Sebastian Michels, Isabelle Monnet, Sanjay Popat, Rafael Rosell, Niki Karachaliou, Sacha I Rothschild, Jin-Yuan Shih, Arne Warth, Thomas Muley, Florian Cabillic, Julien Mazières, Alexander Drilon
Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement...
May 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28444644/ponatinib-in-japanese-patients-with-philadelphia-chromosome-positive-leukemia-a-phase-1-2-study
#2
Arinobu Tojo, Taiichi Kyo, Kazuhito Yamamoto, Hirohisa Nakamae, Naoto Takahashi, Yukio Kobayashi, Tetsuzo Tauchi, Shinichiro Okamoto, Koichi Miyamura, Kiyohiko Hatake, Hiromi Iwasaki, Itaru Matsumura, Noriko Usui, Tomoki Naoe, Meera Tugnait, Narayana I Narasimhan, Stephanie Lustgarten, Heinrich Farin, Frank Haluska, Kazuma Ohyashiki
In this ongoing Phase 1/2 study (NCT01667133), we evaluated ponatinib and assessed its recommended dose in Japanese patients with chronic myeloid leukemia (CML) resistant/intolerant to dasatinib or nilotinib, or with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) resistant/intolerant to ≥1 tyrosine kinase inhibitor (TKI). The primary endpoints were safety of the recommended dose (Phase 1) and major cytogenetic response (MCyR) by 12 months in chronic-phase CML (CP-CML) patients or major hematologic response (MaHR) by 6 months in patients with advanced phase disease (Phase 2)...
April 25, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28427224/ponatinib-promotes-a-g1-cell-cycle-arrest-of-merlin-nf2-deficient-human-schwann-cells
#3
Alejandra M Petrilli, Jeanine Garcia, Marga Bott, Stephani Klingeman Plati, Christine T Dinh, Olena R Bracho, Denise Yan, Bing Zou, Rahul Mittal, Fred F Telischi, Xue-Zhong Liu, Long-Sheng Chang, D Bradley Welling, Alicja J Copik, Cristina Fernández-Valle
Neurofibromatosis type 2 (NF2) is a genetic syndrome that predisposes individuals to multiple benign tumors of the central and peripheral nervous systems, including vestibular schwannomas. Currently, there are no FDA approved drug therapies for NF2. Loss of function of merlin encoded by the NF2 tumor suppressor gene leads to activation of multiple mitogenic signaling cascades, including platelet-derived growth factor receptor (PDGFR) and SRC in Schwann cells. The goal of this study was to determine whether ponatinib, an FDA-approved ABL/SRC inhibitor, reduced proliferation and/or survival of merlin-deficient human Schwann cells (HSC)...
March 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416739/tki-rotation-induced-persistent-deep-molecular-response-in-multi-resistant-blast-crisis-of-ph-cml
#4
Peter Valent, Susanne Herndlhofer, Mathias Schneeweiß, Bernd Boidol, Anna Ringler, Stefan Kubicek, Karoline V Gleixner, Gregor Hoermann, Emir Hadzijusufovic, Leonhard Müllauer, Wolfgang R Sperr, Giulio Superti-Furga, Christine Mannhalter
In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415816/targeting-the-pim-protein-kinases-for-the-treatment-of-a-t-cell-acute-lymphoblastic-leukemia-subset
#5
Sathish K R Padi, Libia A Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H Song, Jon C Aster, Xue-Zhong Yu, Shikhar Mehrotra, Andrew S Kraft
New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28387926/overall-survival-with-ponatinib-versus-allogeneic-stem-cell-transplantation-in-philadelphia-chromosome-positive-leukemias-with-the-t315i-mutation
#6
Franck E Nicolini, Grzegorz W Basak, Dong-Wook Kim, Eduardo Olavarria, Javier Pinilla-Ibarz, Jane F Apperley, Timothy Hughes, Dietger Niederwieser, Michael J Mauro, Charles Chuah, Andreas Hochhaus, Giovanni Martinelli, Maral DerSarkissian, Mei Sheng Duh, Lisa J McGarry, Hagop M Kantarjian, Jorge E Cortes
BACKGROUND: Effective treatment options for patients with chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) who have the threonine to isoleucine mutation at codon 315 (T315I) are few. The objective of this study was to compare overall survival (OS) between patients with CML and those with Ph+ ALL who received treatment with ponatinib versus allogeneic stem cell transplantation (allo-SCT). METHODS: A post hoc, retrospective, indirect comparison of OS among patients who received single-agent ponatinib in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial with those who underwent allo-SCT as reported to the European Bone Marrow Transplant registry, stratified by CML disease phase and Ph+ ALL, was conducted...
April 7, 2017: Cancer
https://www.readbyqxmd.com/read/28377326/treatment-and-molecular-monitoring-update-in-chronic-myeloid-leukemia-management
#7
Nathalie Sorel, Émilie Cayssials, Françoise Brizard, Jean-Claude Chomel
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from the t(9;22)(q34;q11) translocation. It is characterized by the presence of the BCR-ABL1 fusion gene encoding the BCR-ABL oncoprotein characterized by a deregulated tyrosine kinase activity. Targeted therapies using tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib, bosutinib, or ponatinib have profoundly changed the natural history of the disease with a major impact on survival. Indeed, most patients diagnosed today can enjoy a near normal life expectancy...
April 1, 2017: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/28334876/pdgfrb-gain-of-function-mutations-in-sporadic-infantile-myofibromatosis
#8
Florence A Arts, Raf Sciot, Bénédicte Brichard, Marleen Renard, Audrey de Rocca Serra, Guillaume Dachy, Laura A Noël, Amélie I Velghe, Christine Galant, Maria Debiec-Rychter, An Van Damme, Miikka Vikkula, Raphaël Helaers, Nisha Limaye, Hélène A Poirel, Jean-Baptiste Demoulin
Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood. Multifocal nodules with visceral lesions are associated with a poor prognosis. A few familial cases have been linked to mutations in various genes including PDGFRB. In this study, we sequenced PDGFRB, which encodes a receptor tyrosine kinase, in 16 cases of myofibromatosis or solitary myofibroma. Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma...
March 3, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28319280/nilotinib-induced-panniculitis-in-a-patient-with-chronic-myelogenous-leukemia
#9
Naomi Kitayama, Atsushi Otsuka, Chiaki Hamamoto, Yo Kaku, Hiroshi Shiragami, Yoshiyuki Okumura, Kaoru Tsujioka
Nilotinib is a second-generation tyrosine kinase inhibitors (TKIs) developed to target the bcr-abl protein for the treatment of chronic myelogenous leukemia (CML). [1] Nilotinib has been described as a well-tolerated drug. The most common non-hematologic side effects are skin rash, pruritus, headache, nausea, and fatigue. Cases of panniculitis induced by the other bcr-able TKIs such as imatinib, dasatinib and ponatinib were rarely described in the literature.[2-5] However, a case of panniculitis induced by nilotinib has not been reported...
March 20, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28316033/cardiovascular-complications-of-targeted-therapies-for-chronic-myeloid-leukemia
#10
REVIEW
Rongras Damrongwatanasuk, Michael G Fradley
The development of tyrosine kinase inhibitors (TKIs) dramatically changed the treatment landscape for many different cancers including chronic myeloid leukemia (CML). With the introduction of imatinib, the first TKI developed and approved to effectively treat CML, patient survival has increased dramatically and, in some cases, this fatal cancer can be managed as a chronic disease. Since the approval of imatinib in 2002, four additional TKIs have been developed to treat this disease including the second-generation TKIs nilotinib, dasatinib, and bosutinib and the third-generation TKI ponatinib...
April 2017: Current Treatment Options in Cardiovascular Medicine
https://www.readbyqxmd.com/read/28278078/presence-of-novel-compound-bcr-abl-mutations-in-late-chronic-and-advanced-phase-imatinib-sensitive-cml-patients-indicates-their-possible-role-in-cml-progression
#11
Afia Muhammad Akram, Zafar Iqbal, Tanveer Akhtar, Ahmed Mukhtar Khalid, Muhammad Farooq Sabar, Mahmood Hussain Qazi, Zeba Aziz, Nadia Sajid, Aamer Aleem, Mahmood Rasool, Muhammad Asif, Saleh Aloraibi, Khaled Aljamaan, Mudassar Iqbal
BCR-ABL kinase domain (KD) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-KD mutations in chronic phase (n = 41), late chronic phase (n = 33) and accelerated phase (n = 16) imatinib responders...
February 21, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28253536/myeloid-neoplasms-with-concurrent-bcr-abl1-and-cbfb-rearrangements-a-series-of-10-cases-of-a-clinically-aggressive-neoplasm
#12
Alireza Salem, Sanam Loghavi, Guilin Tang, Yang O Huh, Elias J Jabbour, Hagop Kantarjian, Wei Wang, Shimin Hu, Rajyalakshmi Luthra, L Jeffrey Medeiros, Joseph D Khoury
Chronic myeloid leukemia (CML) is defined by the presence of t(9;22)(q34;q11.2)/BCR-ABL1. Additional chromosomal abnormalities confer an adverse prognosis and are particularly common in the blast phase of CML (CML-BP). CBFB rearrangement, particularly CBFB-MYH11 fusion resulting from inv(16)(p13.1q22) or t(16;16)(p13.1;q22), is an acute myeloid leukemia (AML)-defining alteration that is associated with a favorable outcome. The co-occurrence of BCR-ABL1 and CBFB rearrangement is extremely rare, and the significance of this finding remains unclear...
March 2, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28243848/new-treatment-strategies-for-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#13
REVIEW
Lalit Saini, Joseph Brandwein
PURPOSE OF REVIEW: To review recent studies that address important questions regarding the treatment of Philadelphia chromosome-positive ALL. RECENT FINDINGS: Less intensive non-myelosuppressive induction approaches can produce comparable anti-leukemic responses with less toxicity. Second-generation tyrosine kinase inhibitors (TKIs) are not clearly associated with superior outcomes compared to imatinib. Ponatinib is associated with lower early relapse rates, but has additional vascular risks...
February 27, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28184964/absorption-metabolism-and-excretion-of-14-c-ponatinib-after-a-single-oral-dose-in-humans
#14
Yihua E Ye, Caroline N Woodward, Narayana I Narasimhan
PURPOSE: Ponatinib is a novel tyrosine kinase inhibitor (TKI) specifically designed to inhibit native and mutated BCR-ABL. In the United States, ponatinib has received accelerated approval for adults with T315I-positive chronic myeloid leukemia (CML) or T315I (gatekeeper mutation)-positive, Philadelphia chromosome-positive, acute lymphoblastic leukemia (Ph + ALL), and patients with CML or Ph + ALL for whom no other TKI therapy is indicated. The objective of this phase 1, mass balance study was to evaluate the absorption, metabolism, and excretion of [(14)C]ponatinib in healthy subjects...
March 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28178968/imatinib-relaxes-the-pulmonary-venous-bed-of-guinea-pigs
#15
Nina A Maihöfer, Said Suleiman, Daniela Dreymüller, Paul W Manley, Rolf Rossaint, Stefan Uhlig, Christian Martin, Annette D Rieg
BACKGROUND: Recently, the IMPRES study revealed that systemic imatinib improves exercise capacity in patients with advanced pulmonary arterial hypertension. Imatinib blocks the tyrosine kinase activity of the platelet-derived growth factor (PDGF)-receptor (PDGFR), acts antiproliferative and relaxes pulmonary arteries. However so far, the relaxant effects of imatinib on pulmonary veins (PVs) and on the postcapillary resistance are unknown, although pulmonary hypertension (PH) due to left heart disease (LHD) is most common and primarily affects PVs...
February 8, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28138694/activity-of-fibroblast-growth-factor-receptor-inhibitors-tki258-ponatinib-and-azd4547-against-tpr%C3%A2-fgfr1-fusion
#16
Xu-Hua Qiu, Feng Li, Hong-Qin Cao, Jing-Jing Shao, Jian-Gang Mei, Han-Qing Li, Yong-Ping Zhai
8p11 myeloproliferative syndrome (EMS) is a rare disease characterized by the constitutive activation of fibroblast growth factor receptor 1 (FGFR1). To date, four cases of EMS with the chromosomal translocation, t(1;8)(q25;p11.2), have been reported. In the present study, TPR‑FGFR1‑expressing Baf3 cells were established and confirmed by polymerase chain reaction. To identify the most promising drug for EMS, the activities and associated mechanism of three tyrosine kinase inhibitors (TKIs), TKI258, ponatinib and AZD4547, against TPR‑FGFR1 were tested by MTT assay, flow cytometry and western blot...
March 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28135648/current-approach-to-the-treatment-of-chronic-myeloid-leukaemia
#17
REVIEW
Ivan Pasic, Jeffrey H Lipton
Of all the cancers, chronic myeloid leukaemia (CML) has witnessed the most rapid evolution of the therapeutic milieu in recent decades. The introduction of tyrosine kinase inhibitors (TKIs) as a therapeutic option has profoundly changed patient experience and outcome. The availability of multiple new highly effective therapies has increasingly underscored the importance of a good understanding of the underlying pathophysiological basis in CML, as well as patient-specific factors in choosing the right treatment for every individual...
April 2017: Leukemia Research
https://www.readbyqxmd.com/read/28094372/theoretical-studies-on-fgfr-isoform-selectivity-of-fgfr1-fgfr4-inhibitors-by-molecular-dynamics-simulations-and-free-energy-calculations
#18
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/28069043/fgf19-fgfr4-signaling-contributes-to-the-resistance-of-hepatocellular-carcinoma-to-sorafenib
#19
Lixia Gao, Xuli Wang, Yaoliang Tang, Shuang Huang, Chien-An Andy Hu, Yong Teng
BACKGROUND: Sorafenib, a multi-kinase inhibitor, is used as a standard therapy for advanced hepatocellular carcinoma (HCC). However, complete remission has not been achieved and the molecular basis of HCC resistance to sorafenib remains largely unknown. Previous studies have shown that fibroblast growth factor 19 (FGF19) expression correlates with tumor progression and poor prognosis of HCC. Here, we demonstrate the novel role of FGF19 in HCC resistance to sorafenib therapy. METHODS: FGF19 Knockdown cells were achieved by lentiviral-mediated interference, and FGFR4 knockout cells were achieved by CRISPR-Cas9...
January 9, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28043854/compound-selectivity-and-target-residence-time-of-kinase-inhibitors-studied-with-surface-plasmon-resonance
#20
Nicole Willemsen-Seegers, Joost C M Uitdehaag, Martine B W Prinsen, Judith R F de Vetter, Jos de Man, Masaaki Sawa, Yusuke Kawase, Rogier C Buijsman, Guido J R Zaman
Target residence time (τ) has been suggested to be a better predictor of the biological activity of kinase inhibitors than inhibitory potency (IC50) in enzyme assays. Surface plasmon resonance binding assays for 46 human protein and lipid kinases were developed. The association and dissociation constants of 80 kinase inhibitor interactions were determined. τ and equilibrium affinity constants (KD) were calculated to determine kinetic selectivity. Comparison of τ and KD or IC50 values revealed a strikingly different view on the selectivity of several kinase inhibitors, including the multi-kinase inhibitor ponatinib, which was tested on 10 different kinases...
February 17, 2017: Journal of Molecular Biology
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