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Qie He, Junfeng Zhu, David Dingli, Jasmine Foo, Kevin Zox Leder
Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib) have been developed to treat Chronic Myeloid Leukemia (CML). Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies...
October 2016: PLoS Computational Biology
Jesus Duque-Afonso, Chiou-Hong Lin, Kyuho Han, Michael C Wei, Jue Feng, Jason Kurzer, Corina Schneidawind, Stephen H K Wong, Michael C Bassik, Michael L Cleary
There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL which result in hyperactivation of the key oncogenic effector enzyme PLCγ2...
October 7, 2016: Cancer Research
Yu Jin Kim, Sungyoul Hong, Minjung Sung, Min Jeong Park, Kyungsoo Jung, Ka-Won Noh, Doo-Yi Oh, Mi-Sook Lee, Ensel Oh, Young Kee Shin, Yoon-La Choi
Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associated with poor overall survival in a multivariate analysis, and this association was strongest in non-smoker female patients with adenocarcinoma (ADC)...
October 14, 2016: Oncotarget
M Herbrink, N de Vries, H Rosing, A D R Huitema, B Nuijen, J H M Schellens, J H Beijnen
BACKGROUND: A liquid chromatography/tandem mass spectrometry assay was developed to facilitate therapeutic drug monitoring (TDM) for 10 anticancer compounds (dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, and vemurafenib) and the active metabolite, N-desethyl-sunitinib. METHODS: The TDM assay is based on reversed-phase chromatography coupled with tandem mass spectrometry in the positive ion mode using multiple-reaction monitoring for analyte quantification...
October 5, 2016: Therapeutic Drug Monitoring
Thomas O'Hare
No abstract text is available yet for this article.
October 15, 2016: Cancer Research
Noriyoshi Iriyama, Yoshihiro Hatta, Masami Takei
It has been shown that an increase in cytotoxic lymphocyte counts in the peripheral blood occurs rapidly after taking dasatinib, but the underlying mechanism is not yet elucidated. To investigate the influence of dasatinib on signal transduction pathways, we investigated the changes in JAK-STAT, mitogen-activated protein kinase (MAPK), and AKT in cytotoxic lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), before and after dasatinib treatment in chronic myeloid leukemia patients...
October 10, 2016: Cancer Medicine
Sapan J Patel, Costel C Darie, Bayard D Clarkson
Tumors contain heterogeneous cell populations and achieve dominance by functioning as collective systems. The mechanisms underlying the aberrant growth and interactions between cells are not very well understood. The pre-B acute lymphoblastic leukemia cells we studied were obtained directly from a patient with Ph+ ALL. A new Ph+ ALL cell line (ALL3) was established from the leukemic cells growing as ascitic cells in his pleural fluid. The patient died of his disease shortly after the cells were obtained. ALL3 cells grow well at high cell densities (HD), but not at low cell densities...
2016: American Journal of Translational Research
Khadega A Abuelgasim, Saeed Alshieban, Nada A Almubayi, Ayman Alhejazi, Abdulrahman R Jazieh
We describe the case of a young man with therapy-naive chronic myeloid leukemia who did not initially have any peripheral blood or bone marrow excess blasts but presented with extramedullary myeloid blast crises involving the central nervous system and multiple lymph nodes. Conventional cytogenetic tests were positive for t(9;22)(q34:q11) as well as for trisomy 8, 14 and 21 and del(16q). The patient's peripheral blood and bone marrow were positive for the BCR-ABL oncogene when analyzed by fluorescence in situ hybridization and polymerase chain reaction...
May 2016: Case Reports in Oncology
Stephanie Bauer, Susan Buchanan, Irene Ryan
Several tyrosine kinase inhibitors (TKIs) are now approved for the treatment of chronic myeloid leukemia in chronic phase. The efficacy of these drugs has been repeatedly demonstrated, as has their tolerability in most patients. However, late and chronic toxicities become an important issue for many patients facing long-term TKI exposure. For patients on long-term imatinib, gastrointestinal events, fluid retention, muscle cramps, fatigue, and hepatotoxicity are among the most common and most clinically relevant adverse events (AEs)...
January 2016: Journal of the Advanced Practitioner in Oncology
Young-Rang Kim, Young Hye Kim, Sung Woo Kim, Yong Ju Lee, Dong-Eon Chae, Kyung-A Kim, Zee-Won Lee, Nam Doo Kim, Jong-Soon Choi, Insung S Choi, Kyung-Bok Lee
Herein, we present a simple readout of the binding between a chemical drug and its target proteins in the cytoplasm by using a two-step bioorthogonal labeling method combined with spatially-localized expression of proteins. Dasatinib was modified with trans-cyclooctene (TCO), and its cytoplasmic target kinases were expressed in intracellular compartments, such as endosomes and F-actins. After bioorthogonal labeling, the colocalization between Dasatinib and its target proteins was observed in intracellular compartments...
September 27, 2016: Chemical Communications: Chem Comm
Stina Söderlund, Lisa Christiansson, Inger Persson, Henrik Hjorth-Hansen, Johan Richter, Bengt Simonsson, Satu Mustjoki, Ulla Olsson-Strömberg, Angelica Loskog
BACKGROUND AND AIMS: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation. METHODS: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib)...
September 27, 2016: Leukemia Research
Victor M Villalobos, Brianna Hoffner, Anthony D Elias
No abstract text is available yet for this article.
October 3, 2016: Cancer
Scott M Schuetze, Vanessa Bolejack, Edwin Choy, Kristen N Ganjoo, Arthur P Staddon, Warren A Chow, Hussein A Tawbi, Brian L Samuels, Shreyaskumar R Patel, Margaret von Mehren, Gina D'Amato, Kirsten M Leu, David M Loeb, Charles A Forscher, Mohammed M Milhem, Daniel A Rushing, David R Lucas, Rashmi Chugh, Denise K Reinke, Laurence H Baker
BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%...
October 3, 2016: Cancer
Brian B Hasinoff, Daywin Patel, Xing Wu
Five clinically approved BCR-ABL1-targeted tyrosine kinase inhibitors (bosutinib, dasatinib, imatinib, nilotinib, and ponatinib) used for treating chronic myelogenous leukemia have been studied in a neonatal rat myocyte model for their relative ability to induce myocyte damage. This was done in order to determine if kinase inhibitor-induced myocyte damage was a consequence of inhibiting ABL1 (on-target effects), or due to a lack of kinase selectivity (off-target effects) since previous studies have come up with conflicting conclusions about whether imatinib-induced cardiotoxicity results directly from inhibition of ABL1...
September 30, 2016: Cardiovascular Toxicology
F Rocchetti, C Tran Quang, A L Maragno, J Nguyen, C Lasgi, J Ghysdael
No abstract text is available yet for this article.
October 21, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Nan-Sheng Li, Nathan Gossai, Jordan A Naumann, Peter M Gordon, Joseph A Piccirilli
Two synthetic approaches to linear dasatinib-DNA conjugates via click chemistry are described. One approach involves the reaction of excess azido dasatinib derivative with 5'-(5-hexynyl) tagged DNAs and the other involves the reaction of excess alkynyl linked dasatinib with 5'-azido tagged DNA. The second approach using alkynyl derived dasatinib and 5'-azido tagged DNA yielded the corresponding dasatinib-DNA conjugates in higher yield (47% versus 10-33% for the first approach). Studies have shown these linear dasatinib-DNA conjugates derived gold nanoparticles exhibit efficacy against leukemia cancer cells with reduced toxicity toward normal cells compared to free dasatinib...
September 30, 2016: Bioconjugate Chemistry
Vino T Cheriyan, Magesh Muthu, Ketan Patel, Sreeja Sekhar, Walajapet Rajeswaran, Scott D Larsen, Lisa Polin, Edi Levi, Mandip Singh, Arun K Rishi
Doxorubicin and Cisplatin are the frontline therapeutics for treatment of the triple negative breast cancers (TNBCs). Emergence of drug-resistance often contributes to failure of drugs and poor prognosis, and thus necessitates development of new and improved modalities to treat TNBCs. We generated and characterized chemotherapy-resistant TNBC cells following their culture in chronic presence of Doxorubicin or Cisplatin, and tested whether their viabilities were inhibited by a novel class of CARP- 1 functional mimetic (CFM) compounds...
September 28, 2016: Oncotarget
Gen Kano, Bruce S Bochner, Nives Zimmermann
RATIONALE: Siglec-8 is a surface receptor predominantly expressed on human eosinophils where its ligation induces reactive oxygen species (ROS) formation and cell death. Since Siglec-8 has intracellular tyrosine-based motifs, we hypothesized that Src family kinases (SFKs) are involved in ROS formation and cell death induced by Siglec-8 engagement. METHODS: Human peripheral blood eosinophils were purified and incubated with anti-Siglec-8 monoclonal antibodies (mAb, agonist), IL-5, and SFK pharmacological inhibitors...
September 20, 2016: Immunobiology
Stefan Vallo, Martin Michaelis, Kilian M Gust, Peter C Black, Florian Rothweiler, Hans-Michael Kvasnicka, Roman A Blaheta, Maximilian P Brandt, Felix Wezel, Axel Haferkamp, Jindrich Cinatl
BACKGROUND: Systemic chemotherapy with gemcitabine and cisplatin is standard of care for patients with metastatic urothelial bladder cancer. However, resistance formation is common after initial response. The protein Src is known as a proto-oncogene, which is overexpressed in various human cancers. Since there are controversial reports about the role of Src in bladder cancer, we evaluated the efficacy of the Src kinase inhibitor dasatinib in the urothelial bladder cancer cell line RT112 and its gemcitabine-resistant sub-line RT112(r)GEMCI(20) in vitro and in vivo...
September 27, 2016: BMC Research Notes
Maki Hagihara, Noriyoshi Iriyama, Chikashi Yoshida, Hisashi Wakita, Shigeru Chiba, Shinichiro Okamoto, Kimihiro Kawakami, Naoki Takezako, Takashi Kumagai, Koiti Inokuchi, Kazuma Ohyashiki, Jun Taguchi, Shingo Yano, Tadahiko Igarashi, Yasuji Kouzai, Satoshi Morita, Junichi Sakamoto, Hisashi Sakamaki
Despite the efficacy and safety of dasatinib treatment for chronic-phase chronic myeloid leukemia (CML-CP), adverse effects such as pleural effusion (PE) are still a serious concern. We determined the clinical significance of PE incidence using patient data derived from the D-First clinical study. In the present study, chest radiography and quantification of specific lymphocyte subsets were performed routinely after initiation of dasatinib treatment. Among 52 patients with newly diagnosed CML-CP, 17 (33%) developed PE within 18 months after initial dasatinib administration, but all cases were moderate (Grade 1, 10 patients; Grade 2, 7 patients)...
September 20, 2016: Oncology Reports
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