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https://www.readbyqxmd.com/read/28810255/ponatinib-induced-graft-versus-host-disease-graft-versus-leukemia-effect-in-a-patient-with-philadelphia-positive-acute-lymphoblastic-leukemia-without-the-t315i-mutation-relapsing-after-allogeneic-transplant
#1
Annamaria Petrungaro, Massimo Gentile, Carla Mazzone, Rosa Greco, Giuseppina Uccello, Anna Grazia Recchia, Laura De Stefano, Sabrina Bossio, Angela Palummo, Rosellina Morelli, Caterina Musolino, Fortunato Morabito, Ernesto Vigna
We describe the case of a patient with Philadelphia-positive acute lymphoblastic leukemia treated with dasatinib plus steroids as first-line therapy, who achieved a major molecular response (MMR) before undergoing matched, unrelated donor allogeneic stem cell transplant. Eleven months after the transplant, she experienced molecular relapse. Mutational screening showed negativity for the T315I mutation, The patient underwent a salvage chemotherapy regimen with clofarabine + cyclophosphamide + steroids and ponatinib (clofarabine 70 mg i...
August 16, 2017: Chemotherapy
https://www.readbyqxmd.com/read/28796569/cost-effectiveness-of-kinase-inhibitors-for-hematologic-malignancies-a-systematic-and-critical-review
#2
Monia Marchetti
Several genetic disruptions lead to constitutive activation of those kinases leukemic cells depend on for survival and proliferation. Kinase inhibitors (KI) are major therapeutic innovations for chronic myeloid leukemia (CML), chronic lymphoid leukemia (CLL) and myelofibrosis (MF) providing a relevant improvement of quality-adjusted survival in patients with high-risk or refractory disease. CML patients are being treated with first-generation KI imatinib since many years, achieving expected survivals longer than 10 years...
August 10, 2017: Expert Review of Pharmacoeconomics & Outcomes Research
https://www.readbyqxmd.com/read/28781850/t315i-clone-selection-in-a-ph-all-patient-under-low-dose-ponatinib-maintenance
#3
Jasmine Noetzli, Mathilde Gavillet, Stavroula Masouridi-Levrat, Michel Duchosal, Olivier Spertini
We report here the clinical course of a Ph+ ALL patient who was treated with ponatinib 15 mg/day, as maintenance therapy, and developed a BCR-ABL T315I mutation leading to ALL relapse. This clonal evolution was reversed, without adverse effects, by increasing ponatinib to 45 mg/day. To our knowledge, we have been confronted with the first clinical case of a T315I clonal selection of ALL caused by subeffective therapeutic level of the drug. This single patient experience highlights the risk of T315I clone selection in Ph+ ALL treated with reduced dose ponatinib...
August 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28756527/synergistic-tumor-suppression-by-a-perilla-frutescens-derived-methoxyflavanone-and-anti-cancer-tyrosine-kinase-inhibitors-in-a549-human-lung-adenocarcinoma
#4
Amer Ali Abd El-Hafeez, Takashi Fujimura, Rikiya Kamei, Noriko Hirakawa, Kenji Baba, Kazuhisa Ono, Seiji Kawamoto
Anti-cancer tyrosine kinase inhibitors (TKIs) are effective in many types of cancers including non-small cell lung cancer, while appearance of TKI-resistant tumors suggests a need for the development of their potentiation strategies. We have previously shown that a methoxyflavanone derivative from the Asian medicinal herb Perilla frutescens (Perilla-derived methoxyflavanone; PDMF) shows a prominent anti-tumor activity against A549 human lung adenocarcinoma. Here we show that PDMF and anti-cancer TKIs (nilotinib, bosutinib, dasatinib, and ponatinib) synergistically suppress proliferation of A549 cells...
July 29, 2017: Cytotechnology
https://www.readbyqxmd.com/read/28751539/mechanisms-of-resistance-to-ntrk-inhibitors-and-therapeutic-strategies-in-ntrk1-rearranged-cancers
#5
Miho J Fuse, Koutaroh Okada, Tomoko Oh-Hara, Hayato Ogura, Naoya Fujita, Ryohei Katayama
Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small-cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKIs), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance...
July 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28728594/implementing-the-efftox-dose-finding-design-in-the-matchpoint-trial
#6
Kristian Brock, Lucinda Billingham, Mhairi Copland, Shamyla Siddique, Mirjana Sirovica, Christina Yap
BACKGROUND: The Matchpoint trial aims to identify the optimal dose of ponatinib to give with conventional chemotherapy consisting of fludarabine, cytarabine and idarubicin to chronic myeloid leukaemia patients in blastic transformation phase. The dose should be both tolerable and efficacious. This paper describes our experience implementing EffTox in the Matchpoint trial. METHODS: EffTox is a Bayesian adaptive dose-finding trial design that jointly scrutinises binary efficacy and toxicity outcomes...
July 20, 2017: BMC Medical Research Methodology
https://www.readbyqxmd.com/read/28714357/pharmaceutical-assistance-programs-for-cancer-patients-in-the-era-of-orally-administered-chemotherapeutics
#7
Aaron Mitchell, Benyam Muluneh, Rachana Patel, Ethan Basch
Introduction The rising cost of cancer drugs may make treatment unaffordable for some patients. Patients often rely on drug manufacturer-administered Pharmaceutical Assistance Programs (PAPs) to obtain drugs and reduced or no cost. The overall usage of PAPs within cancer care delivery is unknown. Methods We included all cancer patients across an academically affiliated, integrated health system in North Carolina during 2014 ( N = 8591). We identified the subset of patients receiving PAP assistance to afford one or more cancer drugs, in order to calculate the proportion of patients receiving PAP assistance, and the retail value of the assistance...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/28690276/pharmacological-characteristics-and-clinical-outcomes-of-ponatinib-iclusig-%C3%A2-a-third-generation-tyrosine-kinase-inhibitor
#8
Takahiro Yoshida, Ei Leen Liew, Mihoko Ota, Hiroshi Nakayama, Yasuo Yanagihara, Yuki Nakamura, Taku Seriu, Masaru Kamishohara
No abstract text is available yet for this article.
2017: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
https://www.readbyqxmd.com/read/28646488/mutation-in-the-fgfr1-tyrosine-kinase-domain-or-inactivation-of-pten-is-associated-with-acquired-resistance-to-fgfr-inhibitors-in-fgfr1-driven-leukemia-lymphomas
#9
John K Cowell, Haiyan Qin, Tianxiang Hu, Qing Wu, Aaron Bhole, Mingqiang Ren
Stem cell leukemia/lymphoma syndrome (SCLL) is driven by constitutive activation of chimeric FGFR1 kinases generated by chromosome translocations. We have shown that FGFR inhibitors significantly suppress leukemia and lymphoma development in vivo, and cell viability in vitro. Since resistance to targeted therapies is a major reason for relapse, we developed FGFR1-overexpressing mouse and human cell lines that are resistant to the specific FGFR inhibitors AZD4547 and BGJ398, as well as non-specific inhibitors, such as ponatinib, TKI258 and E3810...
June 24, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28639957/pulmonary-arterial-hypertension-induced-by-tyrosine-kinase-inhibitors
#10
Jason Weatherald, Marie-Camille Chaumais, David Montani
PURPOSE OF REVIEW: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of several neoplastic conditions; however, pulmonary arterial hypertension (PAH) has been reported as a complication of TKIs, predominantly with dasatinib. Recent studies have elucidated the potential mechanisms of TKI-induced PAH and have better clarified the long-term outcomes. RECENT FINDINGS: In addition to the known association between dasatinib and PAH, several other TKIs have recently been reported to cause PAH, including ponatinib, bosutinib and lapatinib...
September 2017: Current Opinion in Pulmonary Medicine
https://www.readbyqxmd.com/read/28619758/co-targeting-of-mek-and-pdgfr-stat3-pathways-to-treat-pancreaticductal-adenocarcinoma
#11
Nisebita Sahu, Emily Chan, Felix Chu, Thinh Pham, Hartmut Koeppen, William Forrest, Mark Merchant, Jeff Settleman
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human diseases and remains largely refractory to available drug treatments.  Insufficient targeting of the known oncogenic drivers and activation of compensatory feedback loops and inability to prevent metastatic spread contribute to poor prognosis for this disease. The KRAS-driven MEK pathway is mutationally activated in most pancreatic cancers and is an important target for therapeutics. Using a 2-dimensional monolayer culture system as well as 3-dimensional spheroid culture system, we conducted a screen of a large panel of anti-cancer agents, and found that MEK inhibitors were most effective in targeting PDAC spheroids in comparison to monolayer cultures...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28615362/drugging-the-catalytically-inactive-state-of-ret-kinase-in-ret-rearranged-tumors
#12
Dennis Plenker, Maximilian Riedel, Johannes Brägelmann, Marcel A Dammert, Rakhee Chauhan, Phillip P Knowles, Carina Lorenz, Marina Keul, Mike Bührmann, Oliver Pagel, Verena Tischler, Andreas H Scheel, Daniel Schütte, Yanrui Song, Justina Stark, Florian Mrugalla, Yannic Alber, André Richters, Julian Engel, Frauke Leenders, Johannes M Heuckmann, Jürgen Wolf, Joachim Diebold, Georg Pall, Martin Peifer, Maarten Aerts, Kris Gevaert, René P Zahedi, Reinhard Buettner, Kevan M Shokat, Neil Q McDonald, Stefan M Kast, Oliver Gautschi, Roman K Thomas, Martin L Sos
Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors...
June 14, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28557248/ponatinib-induced-widespread-ichthyosiform-eruption
#13
F Derlino, S Barruscotti, P Zappasodi, V Brazzelli, C Vassallo
Ponatinib is a new potent third-generation tyrosine kinase inhibitor (TKI), developed for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukaemia (ALL) resistant to first (imatinib) and second generation (dasatinib and nilotinib) TK-inhibitors. Aimed at wild type and mutant BCR-ABL, ponatinib demonstrates significant anti-leukemic activity and holds much promise in treating other malignancies, including gastrointestinal stromal tumors (GIST)(1;2). This article is protected by copyright...
May 30, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28549238/risk-factors-and-mechanisms-contributing-to-tki-induced-vascular-events-in-patients-with-cml
#14
REVIEW
Peter Valent, Emir Hadzijusufovic, Gregor Hoermann, Wolfgang Füreder, Gerit-Holger Schernthaner, Wolfgang R Sperr, Rudolf Kirchmair, Dominik Wolf
Vascular adverse events (VAE) are an emerging problem in patients with chronic myeloid leukemia (CML) receiving second-generation BCR-ABL1 tyrosine kinase inhibitors (TKI). Relevant VAE comprise peripheral, cerebral, and coronary artery changes in patients receiving nilotinib, venous and arterial occlusive events during ponatinib therapy, and pulmonary hypertension in patients receiving dasatinib. Although each TKI binds to a unique profile of molecular targets in leukemic cells and vascular cells, the exact etiology of drug-induced vasculopathies remains uncertain...
May 12, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28531278/cardiovascular-toxic-effects-of-targeted-cancer-therapy
#15
Kazuko Tajiri, Kazutaka Aonuma, Ikuo Sekine
Over the past decade, there has been a major shift in chemotherapy from non-specific cytotoxic drugs to molecular targeted drug therapies. As more molecular targeted therapies are developed, new types of cardiovascular toxicities induced by targeted therapies are a growing problem. Cardiotoxicity induced by the human epidermal growth factor receptor-2 inhibitor trastuzumab manifests as decreased left ventricular ejection fraction. In contrast to anthracycline treatment, most cardiac events occur during trastuzumab treatment, but are reversed quickly when treatment is interrupted and cardiac intervention is established...
May 20, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28521421/an-unusual-translocation-t-1-11-q21-q23-in-a-case-of-chronic-myeloid-leukemia-with-a-cryptic-philadelphia-chromosome
#16
Leandro Germán Gutiérrez, María Fernanda Noriega, Alejandro Laudicina, Mariana Quatrin, Raquel María Bengió, Irene Larripa
Chronic myeloid leukemia (CML) is characterized by the translocation t(9;22)(q34;q11) [Philadelphia (Ph) chromosome). Although not frequently occurring, additional chromosome abnormalities (ACAs) can be detected at diagnosis and a number have been associated with an adverse cytogenetic and molecular outcome. The present study reports a case of CML presenting with the translocation t(1;11)(q21;q23) and a cryptic Ph chromosome. The presence of ACAs could generate greater genetic instability, promoting the emergence of further alterations...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28520795/birc6-mediates-imatinib-resistance-independently-of-mcl-1
#17
Denis O Okumu, Michael P East, Merlin Levine, Laura E Herring, Raymond Zhang, Thomas S K Gilbert, David W Litchfield, Yanping Zhang, Lee M Graves
Baculoviral IAP repeat containing 6 (BIRC6) is a member of the inhibitors of apoptosis proteins (IAPs), a family of functionally and structurally related proteins that inhibit apoptosis. BIRC6 has been implicated in drug resistance in several different human cancers, however mechanisms regulating BIRC6 have not been extensively explored. Our phosphoproteomic analysis of an imatinib-resistant chronic myelogenous leukemia (CML) cell line (MYL-R) identified increased amounts of a BIRC6 peptide phosphorylated at S480, S482, and S486 compared to imatinib-sensitive CML cells (MYL)...
2017: PloS One
https://www.readbyqxmd.com/read/28500237/resistance-to-ret-inhibition-in-ret-rearranged-nsclc-is-mediated-by-reactivation-of-ras-mapk-signaling
#18
Sarah K Nelson-Taylor, Anh T Le, Minjae Yoo, Laura Schubert, Katie M Mishall, Andrea Doak, Marileila Varella-Garcia, Aik-Choon Tan, Robert C Doebele
Oncogenic rearrangements in RET are present in 1%-2% of lung adenocarcinoma patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent antiproliferative activity in RET fusion-positive LC-2/ad lung adenocarcinoma cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived...
August 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28475010/computational-analysis-of-abl-kinase-mutations-allows-predicting-drug-sensitivity-against-selective-kinase-inhibitors
#19
Swapna Kamasani, Sravani Akula, Sree Kanth Sivan, Vijjulatha Manga, Justus Duyster, Dashavantha Reddy Vudem, Rama Krishna Kancha
The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive chronic myeloid leukemia. However, a significant proportion of imatinib-treated patients relapse due to occurrence of mutations in the ABL kinase domain. Although inhibitor sensitivity for a set of mutations was reported, the role of less frequent ABL kinase mutations in drug sensitivity/resistance is not known. Moreover, recent reports indicate distinct resistance profiles for second-generation ABL inhibitors. We thus employed a computational approach to predict drug sensitivity of 234 point mutations that were reported in chronic myeloid leukemia patients...
May 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28467002/the-use-of-imatinib-resistance-mutation-analysis-to-direct-therapy-in-philadelphia-chromosome-bcr-abl1-positive-chronic-myeloid-leukaemia-patients-failing-imatinib-treatment-in-patan-hospital-nepal
#20
REVIEW
Gyan K Kayastha, Nora Ranjitkar, Radha Gurung, Raj Kumar Kc, Sanjit Karki, Roshan Shrestha, Piyush Rajbhandari, Raj K Thapa, Buddhi Poudyal, Paras Acharya, David J Roberts, Bruce Hayes, Mark Zimmerman, Buddha Basnyat
Philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukaemia (CML) can be successfully treated with Glivec (Imatinib), which is available free of cost through the Glivec International Patient Assistance programme (GIPAP) to patients with proven CML without means to pay for the drug. We review the acquired mutations in the tyrosine kinase encoded by the BCR-ABL1 gene underlying Glivec failure or resistance in a cohort of 388 imatinib-treated CML patients (149 Female and 239 male) registered between February 2003 and June 2016 in Nepal...
June 2017: British Journal of Haematology
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