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https://www.readbyqxmd.com/read/28334876/pdgfrb-gain-of-function-mutations-in-sporadic-infantile-myofibromatosis
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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...
January 24, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28135648/current-approach-to-the-treatment-of-chronic-myeloid-leukaemia
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/28032146/effects-of-31-fda-approved-small-molecule-kinase-inhibitors-on-isolated-rat-liver-mitochondria
#14
Jun Zhang, Alec Salminen, Xi Yang, Yong Luo, Qiangen Wu, Matthew White, James Greenhaw, Lijun Ren, Matthew Bryant, William Salminen, Thomas Papoian, William Mattes, Qiang Shi
The FDA has approved 31 small-molecule kinase inhibitors (KIs) for human use as of November 2016, with six having black box warnings for hepatotoxicity (BBW-H) in product labeling. The precise mechanisms and risk factors for KI-induced hepatotoxicity are poorly understood. Here, the 31 KIs were tested in isolated rat liver mitochondria, an in vitro system recently proposed to be a useful tool to predict drug-induced hepatotoxicity in humans. The KIs were incubated with mitochondria or submitochondrial particles at concentrations ranging from therapeutic maximal blood concentrations (Cmax) levels to 100-fold Cmax levels...
December 28, 2016: Archives of Toxicology
https://www.readbyqxmd.com/read/28006933/nilotinib-induces-er-stress-and-cell-death-in-h9c2-cells
#15
D Lekes, I Szadvari, O Krizanova, K Lopusna, I Rezuchova, M Novakova, Z Novakova, T Parak, P Babula
Tyrosine kinases inhibitors (TKi) represent a relatively novel class of anticancer drugs that target cellular pathways overexpressed in certain types of malignancies, such as chronic myeloid leukaemia (CML). Nilotinib, ponatinib and imatinib exhibit cardiotoxic and vascular effects. In this study, we focused on possible cardiotoxicity of nilotinib using H9c2 cells as a suitable cell model. We studied role of endoplasmic reticulum (ER) stress and apoptosis in nilotinib toxicity using a complex approach. Nilotinib impaired mitochondrial function and induced formation of ROS under clinically relevant concentrations...
December 21, 2016: Physiological Research
https://www.readbyqxmd.com/read/28006851/poor-outcomes-associated-with-der-22-t-9-22-and-9-9p-in-patients-with-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-receiving-chemotherapy-plus-a-tyrosine-kinase-inhibitor
#16
Nicholas J Short, Hagop M Kantarjian, Koji Sasaki, Farhad Ravandi, Heidi Ko, C Cameron Yin, Guillermo Garcia-Manero, Jorge E Cortes, Rebecca Garris, Susan M O'Brien, Keyur Patel, Maria Khouri, Deborah Thomas, Nitin Jain, Tapan M Kadia, Naval Daver, Christopher B Benton, Ghayas C Issa, Marina Konopleva, Elias Jabbour
In patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well-established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first-line intensive chemotherapy plus either imatinib (n=36), dasatinib (n=74) or ponatinib (n=42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse-free survival (RFS; P=0...
December 22, 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27971669/matching-adjusted-indirect-comparison-maic-analysis-for-ponatinib-vs-bosutinib-in-third-line-chronic-phase-chronic-myeloid-leukemia-cp-cml
#17
S Iannazzo, L McGarry, S Lustgarten, S Chiroli
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27957861/codelivery-of-ponatinib-and-sar302503-by-active-bone-targeted-polymeric-micelles-for-the-treatment-of-therapy-resistant-chronic-myeloid-leukemia
#18
Chao-Feng Mu, Yang Xiong, Xue Bai, Yun-Jie Sheng, Jiajun Cui
Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine-dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation...
January 3, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27928806/-molecular-mechanism-of-gastrointestinal-stromal-tumors-and-progress-in-drug-research
#19
Jian Li
The functional mutation of c-kit and platelet-derived growth factor receptor α (PDGFRA) which encode proto-oncogene receptor tyrosine kinase are the crucial pathogeneses of gastrointestinal stromal tumors(GISTs). 80%-85% c-kit gene mutation including exon 11,exon 9,exon 13,exon 17 and 5%-10% PDGFRA gene mutation such as exon 18, exon 12 are examined in GISTs. Neither of c-kit or PDGFRA gene mutation are called wide type GISTs. The pathogeneses of wild type GISTs are not clear. The deficiency of succinate dehydrogenase B(SDHB)-related insulin-like growth factor 1(IGF-1R) activation, BRAF gene mutation and neurofibromatosis type 1 may be related to progression of wild type GISTs...
November 25, 2016: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/27901368/second-line-small-molecule-therapy-options-for-treating-chronic-myeloid-leukemia
#20
REVIEW
Matteo Molica, Fulvio Massaro, Massimo Breccia
Approximately 33% of chronic myeloid leukemia (CML) patients discontinue treatment with imatinib in the long-term due to resistance and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) have added complexity to the treatment paradigm for this disease. Areas covered: Second generation TKIs, approved as second-line treatment in all phases of the disease, are highly effective in patients resistant to and/or intolerant to imatinib and are extremely active against all the resistant BCR-ABL1 mutations, with the exception of T3151...
January 2017: Expert Opinion on Pharmacotherapy
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