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https://www.readbyqxmd.com/read/29675955/rapid-identification-of-bcr-abl1-like-acute-lymphoblastic-leukaemia-patients-using-a-predictive-statistical-model-based-on-quantitative-real-time-polymerase-chain-reaction-clinical-prognostic-and-therapeutic-implications
#1
Sabina Chiaretti, Monica Messina, Sara Grammatico, Alfonso Piciocchi, Anna L Fedullo, Filomena Di Giacomo, Nadia Peragine, Valentina Gianfelici, Alessia Lauretti, Rohan Bareja, Maria P Martelli, Marco Vignetti, Valerio Apicella, Antonella Vitale, Loretta S Li, Cyril Salek, Olivier Elemento, Giorgio Inghirami, David M Weinstock, Anna Guarini, Robin Foà
BCR/ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B-lineage acute lymphoblastic leukaemia that occurs within cases without recurrent molecular rearrangements. Gene expression profiling (GEP) can identify these cases but it is expensive and not widely available. Using GEP, we identified 10 genes specifically overexpressed by BCR/ABL1-like ALL cases and used their expression values - assessed by quantitative real time-polymerase chain reaction (Q-RT-PCR) in 26 BCR/ABL1-like and 26 non-BCR/ABL1-like cases to build a statistical "BCR/ABL1-like predictor", for the identification of BCR/ABL1-like cases...
April 19, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29675611/ponatinib-as-second-line-treatment-in-chronic-phase-chronic-myeloid-leukemia-patients-in-real-life-practice
#2
Massimo Breccia, Elisabetta Abruzzese, Fausto Castagnetti, Massimiliano Bonifacio, Domenica Gangemi, Federica Sorà, Alessandra Iurlo, Luigiana Luciano, Antonella Gozzini, Massimo Gentile, Monica Bocchia, Debora Luzi, Alessandro Maggi, Nicola Sgherza, Alessandro Isidori, Monica Crugnola, Patrizia Pregno, Anna Rita Scortechini, Isabella Capodanno, Michele Pizzuti, Robin Foà
Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32-72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance...
April 19, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29667003/chemical-genomics-reveals-inhibition-of-breast-cancer-lung-metastasis-by-ponatinib-via-c-jun
#3
Wei Shao, Shasha Li, Lu Li, Kequan Lin, Xinhong Liu, Haiyan Wang, Huili Wang, Dong Wang
Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for anti-metastatic treatment. In our study, high-throughput sequencing-based high-throughput screening (HTS2 ) and a breast cancer lung metastasis (BCLM)-associated gene signature were combined to discover anti-metastatic drugs. After screening of thousands of compounds, we identified Ponatinib as a BCLM inhibitor. Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models...
April 17, 2018: Protein & Cell
https://www.readbyqxmd.com/read/29608815/alkynylnicotinamide-based-compounds-as-abl1-inhibitors-with-potent-activities-against-drug-resistant-cml-harboring-abl1-t315i-mutant-kinase
#4
Herman O Sintim, Elizabeth Larocque, N Naganna, Clement Opoku-Temeng, Alyssa Lambrecht
The introduction of imatinib into the clinical scene revolutionized cancer treatment of chronic myeloid leukemia (CML). The overall 8-year survival rate for CML has increased from about 6% in the 1970s to over 90% in the imatinib era. However, about 20% of CML patients harbor primary or acquired resistance to tyrosine kinase inhibitors. ABL1 point mutations in the BCR-ABL1 fusion protein, such as ABL1(T315I), typically emerge after prolonged kinase inhibitor treatment. Ponatinib (AP24534) is currently the only approved CML drug that is active against the ABL1(T315I) mutation...
April 2, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29567798/ponatinib-efficacy-and-safety-in-philadelphia-chromosome-positive-leukemia-final-5-year-results-of-the-phase-2-pace-trial
#5
Jorge E Cortes, Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D le Coutre, Ronald Paquette, Charles Chuah, Franck E Nicolini, Jane F Apperley, H Jean Khoury, Moshe Talpaz, Daniel J DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Victor M Rivera, Frank G Haluska, François Guilhot, Michael W Deininger, Andreas Hochhaus, Timothy P Hughes, Neil P Shah, Hagop M Kantarjian
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I The pivotal phase 2 PACE trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia resistant/intolerant to dasatinib or nilotinib, or with BCR ABL1T315I This analysis focuses on chronic-phase CML (CP-CML) patients (n=270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and MR4...
March 22, 2018: Blood
https://www.readbyqxmd.com/read/29555876/identification-and-characterization-of-novel-receptor-interacting-serine-threonine-protein-kinase-2-ripk2-inhibitors-using-structural-similarity-analysis
#6
Mohamed Salla, Rodrigo Aguayo-Ortiz, Danmaliki Gaddafi Ibrahim, Alaa Zare, Ahmed Said, Jack Moore, Vrajeshkumar Pandya, Robin Manaloor, Sunny Fong, Anna R Blankstein, Spencer Gibson, Laura Ramos Garcia, Pascal Meier, Khushwant S Bhullar, Basil P Hubbard, Yahya Fiteh, Harissios Vliagoftis, Ing Swie Goping, Dion Brocks, Peter Hwang, Jose Carlos A Martinez Velazquez, Shairaz Baksh
Receptor interacting protein kinase 2 (RIP2 or RICK herein referred to as RIPK2) is linked to the pathogen pathway that activates NFkB and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses we utilized the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% as well as inhibition of NFkB activity...
March 19, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29519619/efficacy-of-ponatinib-versus-earlier-generation-tyrosine-kinase-inhibitors-for-front-line-treatment-of-newly-diagnosed-philadelphia-positive-acute-lymphoblastic-leukemia
#7
Elias Jabbour, Maral DerSarkissian, Mei Sheng Duh, Nora McCormick, Wendy Y Cheng, Lisa J McGarry, Ariadne Souroutzidis, Hui Huang, Susan O'Brien, Farhad Ravandi, Hagop M Kantarjian
INTRODUCTION: Complete molecular response (CMR) and 2- and 3-year overall survival (OS) were compared for patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) who had undergone front-line combination chemotherapy plus ponatinib versus combination therapy plus earlier generation tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, and nilotinib). PATIENTS AND METHODS: We identified 26 Ph+ ALL studies: 25 of earlier generation TKIs and 1 of ponatinib...
February 17, 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29508628/drug-associated-pulmonary-arterial-hypertension
#8
Michael McGee, Nicholas Whitehead, Jennifer Martin, Nicholas Collins
INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence. OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension...
March 6, 2018: Clinical Toxicology
https://www.readbyqxmd.com/read/29502175/ponatinib-for-treating-acute-lymphoblastic-leukaemia-an-evidence-review-group-perspective-of-a-nice-single-technology-appraisal
#9
REVIEW
Matt Stevenson, Abdullah Pandor, Jean Hamilton, John Stevens, Clare Rowntree, Marrissa Martyn-St James, Andrew Rawdin, Ruth Wong
As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (Incyte Corporation) of ponatinib (Inclusig® ) to submit evidence of its clinical and cost effectiveness for previously treated Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and chronic myeloid leukaemia. This paper focusses on Ph+ ALL. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent evidence review group (ERG)...
March 3, 2018: PharmacoEconomics
https://www.readbyqxmd.com/read/29480454/ponatinib-for-treating-chronic-myeloid-leukaemia-an-evidence-review-group-perspective-of-a-nice-single-technology-appraisal
#10
REVIEW
Abdullah Pandor, Matt Stevenson, John Stevens, Marrissa Martyn-St James, Jean Hamilton, Jenny Byrne, Claudius Rudin, Andrew Rawdin, Ruth Wong
As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures ponatinib (Inclusig® ; Incyte Corporation) to submit evidence for the clinical and cost effectiveness for previously treated chronic myeloid leukaemia (CML) and Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). This paper focusses on the three phases of CML: the chronic phase (CP), the accelerated phase (AP) and the blast crisis phase (BP)...
February 26, 2018: PharmacoEconomics
https://www.readbyqxmd.com/read/29479884/extramedullary-blast-crisis-in-a-patient-with-t315i-bcr-abl-mutated-chronic-myeloid-leukemia
#11
Jingwen Zhang, Xiangzhong Zhang, Ying Lu, Ju Jiao, Yuxin Chen, Dongjun Lin
BACKGROUND: Extramedullary blast crisis (EBC) of T315I BCR-ABL mutated chronic myelogenous leukemia (CML) is extremely rare. METHODS: We report an unusual case characterized by fever, right shoulder swelling, pleural effusion, and multiple bone destruction as the first signs of EBC of T315I BCR-ABL mutated CML. RESULTS: The patient did not respond to chemotherapy consisting of anthracyclines, cytarabine and etoposide. His condition improved after the treatment with ponatinib combined with allogenic stem cell transplantation (alloHCT), but soon worsened after ponatinib withdrawal...
January 1, 2018: Clinical Laboratory
https://www.readbyqxmd.com/read/29469781/ponatinib-induced-ichthyosiform-drug-eruption-insights-into-acquired-ichthyosis
#12
Haoming Xu, Klaus J Busam, Michael J Mauro, Alina Markova
Cutaneous adverse events are commonly experienced with use of tyrosine kinase inhibitors in the treatment of leukemia and typically include nonspecific cutaneous eruptions and xerosis. We report the case of a man who experienced an ichthyosiform drug eruption while taking ponatinib, a third-generation tyrosine kinase inhibitor. Disruption of epidermal growth pathways through inhibition of various receptor tyrosine kinases by ponatinib may offer insights into the pathophysiologic mechanisms behind acquired ichthyosis...
October 15, 2017: Dermatology Online Journal
https://www.readbyqxmd.com/read/29464983/repurposing-anticancer-drugs-for-targeting-necroptosis
#13
Simone Fulda
Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases...
February 21, 2018: Cell Cycle
https://www.readbyqxmd.com/read/29463017/identification-of-novel-protein-kinase-receptor-type-2-inhibitors-using-pharmacophore-and-structure-based-virtual-screening
#14
Josiane V Cruz, Moysés F A Neto, Luciane B Silva, Ryan da S Ramos, Josivan da S Costa, Davi S B Brasil, Cleison C Lobato, Glauber V da Costa, José Adolfo H M Bittencourt, Carlos H T P da Silva, Franco H A Leite, Cleydson B R Santos
The Protein Kinase Receptor type 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases; it signals downstream of the NOD1 and NOD2 intracellular sensors and promotes a productive inflammatory response. However, excessive NOD2 signaling has been associated with various diseases, including sarcoidosis and inflammatory arthritis; the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of pro-inflammatory secretion activity. In this study, a pharmacophoric model based on the crystallographic pose of ponatinib, a potent RIPK2 inhibitor, and 30 other ones selected from the BindingDB repository database, was built...
February 18, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29458050/investigation-of-metabolic-stability-of-the-novel-alk-inhibitor-brigatinib-by-liquid-chromatography-tandem-mass-spectrometry
#15
Hany W Darwish, Adnan A Kadi, Mohamed W Attwa, Halah S Almutairi
Brigatinib (BGB) belongs to a class of drugs called ALK inhibitor. On April 28, 2017, BGB has been approved by U.S. FDA for use in metastatic ALK-positive NSCLC. A fast, specific, sensitive and validated LC-MS/MS method was developed for the quantification of BGB in human plasma matrix. This method was applied successfully to study metabolic stability of BGB. Reversed phase (C18 column) and isocratic binary mobile phase (55% 0.1% formic acid: 45% ACN) were used for chromatographic separation of BGB and ponatinib (IS)...
February 16, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29454474/cardiovascular-pulmonary-and-metabolic-toxicities-complicating-tyrosine-kinase-inhibitor-therapy-in-chronic-myeloid-leukemia-strategies-for-monitoring-detecting-and-managing
#16
REVIEW
Bruno C Medeiros, Jennifer Possick, Michael Fradley
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, the incidence of which increases with age. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment, including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. Beyond matching patient disease profiles with TKI specificity, differences in the efficacy and toxicity profiles and a patient's comorbid risk factors should be considered when selecting the most appropriate agent. Our objectives are to review the incidence and severity of cardiovascular, metabolic, and pulmonary disorders associated with these TKIs, highlighting differences in adverse event profiles, suggested risk-mitigation strategies, and guidance for TKI selection in different settings...
February 3, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29440450/pharmacokinetic-assessment-of-cooperative-efflux-of-the-multitargeted-kinase-inhibitor-ponatinib-across-the-blood-brain-barrier
#17
Janice K Laramy, Minjee Kim, Karen E Parrish, Jann N Sarkaria, William F Elmquist
A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [ Mdr1a/b(-/-)Bcrp1(-/-) ] compared with the wild-type mice...
May 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29440177/ponatinib-shows-potent-antitumor-activity-in-small-cell-carcinoma-of-the-ovary-hypercalcemic-type-sccoht-through-multikinase-inhibition
#18
Jessica D Lang, William P D Hendricks, Krystal A Orlando, Hongwei Yin, Jeffrey Kiefer, Pilar Ramos, Ritin Sharma, Patrick Pirrotte, Elizabeth A Raupach, Chris Sereduk, Nanyun Tang, Winnie S Liang, Megan Washington, Salvatore J Facista, Victoria L Zismann, Emily M Cousins, Michael B Major, Yemin Wang, Anthony N Karnezis, Aleksandar Sekulic, Ralf Hass, Barbara C Vanderhyden, Praveen Nair, Bernard E Weissman, David G Huntsman, Jeffrey M Trent
Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT...
February 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29434033/-pdgfrb-mutation-and-tyrosine-kinase-inhibitor-resistance-in-ph-like-acute-lymphoblastic-leukemia
#19
Yingchi Zhang, Yufeng Gao, Hui Zhang, Jingliao Zhang, Fuhong He, Aleš Hnízda, Maoxiang Qian, Xiaoming Liu, Yoshihiro Gocho, Ching-Hon Pui, Tao Cheng, Qianfei Wang, Jun J Yang, Xiaofan Zhu, Xin Liu
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) comprises of approximately 10-15% of childhood ALL cases, many of whom respond exquisitely to tyrosine kinase inhibitors (TKIs), e.g., imatinib in PDGFRB -rearranged ALL. However, some cases developed drug resistance to TKIs with mechanisms poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB , and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation PDGFRBC843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib...
February 6, 2018: Blood
https://www.readbyqxmd.com/read/29423571/novel-therapies-for-older-adults-with-acute-lymphoblastic-leukemia
#20
REVIEW
Nicholas J Short, Hagop Kantarjian, Elias Jabbour, Farhad Ravandi
PURPOSE OF REVIEW: Older adults with acute lymphoblastic leukemia (ALL) have worse survival compared to their younger counterparts. Here, we review the reasons for the poorer outcomes of older patients with ALL and also summarize the current and future therapeutic approaches to ALL in the elderly population. RECENT FINDINGS: The poor outcomes of older adults with ALL are driven largely by lack of tolerance to standard-dose chemotherapy, which leads to unacceptably high rates of myelosuppression-related deaths...
February 8, 2018: Current Hematologic Malignancy Reports
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