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A Antar, Z K Otrock, J El-Cheikh, M A Kharfan-Dabaja, G Battipaglia, R Mahfouz, M Mohty, A Bazarbachi
FMS-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in AML. FLT3 is mutated in ~30% of patients with AML, either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or by a point mutation, usually involving the tyrosine kinase domain. Several FLT3 tyrosine kinase inhibitors are being evaluated in multiple studies aiming at improving outcomes. The most widely used is sorafenib, a potent multikinase inhibitor approved for hepatocellular carcinoma and renal cell carcinoma...
October 24, 2016: Bone Marrow Transplantation
Zhujun Ao, Rong Zhu, Xiaoli Tan, Lisa Liu, Liyu Chen, Shuiping Liu, XiaoJian Yao
BACKGROUND: HIV-1 latency is a major obstacle for HIV-1 eradication. Extensive efforts are being directed toward the reactivation of latent HIV reservoirs with the aim of eliminating latently infected cells via the host immune system and/or virus-mediated cell lysis. RESULTS: We screened over 1,500 small molecules and kinase inhibitors and found that a small molecule, PKC412 (midostaurin, a broad-spectrum kinase inhibitor), can stimulate viral transcription and expression from the HIV-1 latently infected ACH2 cell line and primary resting CD4+ T cells...
October 21, 2016: Virology Journal
Animesh Pardanani
: Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant...
November 2016: American Journal of Hematology
Mona Hassanein, Muhamad H Almahayni, Syed O Ahmed, Sameh Gaballa, Riad El Fakih
FLT3 (Fms-like tyrosine kinase 3) inhibitors are tyrosine kinase inhibitors. The first-generation FLT3 inhibitors were developed several years ago and include midostaurin, lestaurtinib, sunitinib, and sorafenib. They are relatively nonspecific for FLT3, with other potential targets that include platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and Janus kinase 2. The second-generation inhibitors, including quizartinib, crenolanib, PLX3397, and ASP2215, are more potent and selective than the first-generation inhibitors...
June 25, 2016: Clinical Lymphoma, Myeloma & Leukemia
Jason Gotlib, Hanneke C Kluin-Nelemans, Tracy I George, Cem Akin, Karl Sotlar, Olivier Hermine, Farrukh T Awan, Elizabeth Hexner, Michael J Mauro, David W Sternberg, Matthieu Villeneuve, Alice Huntsman Labed, Eric J Stanek, Karin Hartmann, Hans-Peter Horny, Peter Valent, Andreas Reiter
BACKGROUND: Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS: We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia...
June 30, 2016: New England Journal of Medicine
Molly Megan Gallogly, Hillard M Lazarus
Acute myeloid leukemia (AML) is a hematologic malignancy that carries a poor prognosis and has garnered few treatment advances in the last few decades. Mutation of the internal tandem duplication (ITD) region of fms-like tyrosine kinase (FLT3) is considered high risk for decreased response and overall survival. Midostaurin is a Type III receptor tyrosine kinase inhibitor found to inhibit FLT3 and other receptor tyrosine kinases, including platelet-derived growth factor receptors, cyclin-dependent kinase 1, src, c-kit, and vascular endothelial growth factor receptor...
2016: Journal of Blood Medicine
D B Lipka, M-C Wagner, M Dziadosz, T Fischer
Leukemia accepted article preview online, 03 May 2016. doi:10.1038/leu.2016.127.
May 3, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Celalettin Ustun, Jason Gotlib, Uday Popat, Andrew Artz, Mark Litzow, Andreas Reiter, Ryotaro Nakamura, Hanneke C Kluin-Nelemans, Srdan Verstovsek, James Gajewski, Miguel-Angel Perales, Tracy George, Tsiporah Shore, Wolfgang Sperr, Wael Saber, Vamsi Kota, Akif Selim Yavuz, Vinod Pullarkat, John Rogosheske, William Hogan, Koen Van Besien, Hans Hagglund, Gandhi Damaj, Michel Arock, Hans-Peter Horny, Dean D Metcalfe, H Joachim Deeg, Steven Devine, Daniel Weisdorf, Cem Akin, Peter Valent
No abstract text is available yet for this article.
August 2016: Biology of Blood and Marrow Transplantation
Phoebe Starr
No abstract text is available yet for this article.
February 2016: American Health & Drug Benefits
Luca Mazzarella
The 57th American Society of Haematology (ASH) meeting held in Orlando, FL was certainly the year when myeloma management changed for good, with a plethora of newly Food and Drug Administration (FDA)-approved drugs showing impressive outcome improvements and the introduction of new techniques for disease monitoring. Also, chimeric antigen receptor (CAR) T cells continued their triumphal march, consolidating their success in lymphoma and chronic lymhocytic leukaemia (CLL) and venturing into new fields such as again multiple myeloma...
2016: Ecancermedicalscience
Alison R Walker, Hongyan Wang, Katherine Walsh, Bhavana Bhatnagar, Sumithira Vasu, Ramiro Garzon, Renee Canning, Susan Geyer, Yue-Zhong Wu, Steven M Devine, Rebecca Klisovic, William Blum, Guido Marcucci
Targeting aberrant tyrosine kinase activity may impact clinical outcome in acute myeloid leukemia (AML). We conducted a phase I study of the tyrosine kinase inhibitor midostaurin with bortezomib alone and in combination with chemotherapy in patients with AML. Patients on dose levels 1 and 2 (DL1 & 2) received midostaurin 50 mg bid and escalating doses of bortezomib (1 to 1.3 mg/m2). Patients on DL3 or higher received midostaurin and bortezomib following chemotherapy with mitoxantrone, etoposide, cytarabine (MEC)...
September 2016: Leukemia & Lymphoma
Yin-Ying Wang, Wan-Ling Sun
FLT3 gene mutations occurred in approximately 30% of acute myeloid leukemia (AML) patients, which is closely associated with the occurrence, development and poor prognosis of AML. The therapy targeting at FLT3 mutations might be a promising treatment for AML. Midostaurin can inhibit the activities of III receptor tyrosine kinase encoded by FLT3 gene, induce cell cycle arrest and has a apoptotic effect on primitive AML cells of FLT3 -mutant, FLT3 wild-type and the expression of FLT3 mutated receptor. In view of this, the association between FLT3 mutations and AML, and research advances and clinical applications of midostaurin on the treatment of AML especially for FLT3 mutated AML, are reviewed...
December 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
Timea Simon, Ciprian Tomuleasa, Anca Bojan, Ioana Berindan-Neagoe, Sanda Boca, Simion Astilean
BACKGROUND: Releasing drug molecules at the targeted location could increase the clinical outcome of a large number of anti-tumor treatments which require low systemic damage and low side effects. Nano-carriers of drugs show great potential for such task due to their capability of accumulating and releasing their payload specifically, at the tumor site. RESULTS: FLT3 inhibitor - gold nanoparticle conjugates were fabricated to serve as vehicles for the delivery of anti-tumor drugs...
December 2015: Nanoscale Research Letters
Jason Gotlib
World Health Organization-defined myeloproliferative neoplasms share a common pathobiologic theme of constitutive activation of tyrosine kinases (TKs). While myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA or PDGFRB exhibit exquisite responsiveness to imatinib, other eosinophilic disorders such as chronic eosinophilic leukemia--not otherwise specified (CEL-NOS) and idiopathic hypereosinophilic syndrome (HES) lack recurrent gene mutations or known druggable targets. In systemic mastocytosis (SM), KIT D816V is identified in ∼ 90% of patients, but demonstrates imatinib resistance...
December 2015: Current Hematologic Malignancy Reports
B Peter, G E Winter, K Blatt, K L Bennett, G Stefanzl, U Rix, G Eisenwort, E Hadzijusufovic, M Gridling, C Dutreix, G Hoermann, J Schwaab, D Radia, J Roesel, P W Manley, A Reiter, G Superti-Furga, P Valent
Proteomic-based drug testing is an emerging approach to establish the clinical value and anti-neoplastic potential of multikinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC(50) values...
February 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Araceli Tobío, Amparo Alfonso, Luis M Botana
PURPOSE: The second generation of tyrosine kinase inhibitors is a group of compounds that inhibit c-kit receptor activity and therefore widely used in the treatment of mastocytosis. In this research, the relationship between the mechanism of action of tyrosine kinase inhibitors and protein kinase C is investigated in HMC-1(560) or HMC-1(560,816) cell lines. RESULTS: From all the tyrosine kinase inhibitors tested, nilotinib is the compound that has the highest cytotoxic effect against HMC-1(560) mast cell line, while midostaurin is the most potent in HMC-1(560,816)...
2015: Immunopharmacology and Immunotoxicology
Masaaki Kawai, Akio Nakashima, Shinji Kamada, Ushio Kikkawa
BACKGROUND: Breast cancer is classified into three subtypes by the expression of biomarker receptors such as hormone receptors and human epidermal growth factor receptor 2. Triple-negative breast cancer (TNBC) expresses none of these receptors and has an aggressive phenotype with a poor prognosis, which is insensitive to the drugs that target the hormone receptors and human epidermal growth factor receptor 2. It is, thus, required to develop an effective therapeutic reagent to treat TNBC...
2015: Journal of Biomedical Science
Fei Yan, Na Shen, Jiuxia Pang, Julian R Molina, Ping Yang, Shujun Liu
Lung cancer cells are sensitive to 5-aza-2'-deoxycytidine (decitabine) or midostaurin (PKC412), because decitabine restores the expression of methylation-silenced tumor suppressor genes, whereas PKC412 inhibits hyperactive kinase signaling, which is essential for cancer cell growth. Here, we demonstrated that resistance to decitabine (decitabine(R)) or PKC412 (PKC412(R)) eventually results from simultaneously remethylated DNA and reactivated kinase cascades. Indeed, both decitabine(R) and PKC412(R) displayed the up-regulation of DNA methyltransferase DNMT1 and tyrosine-protein kinase KIT, the enhanced phosphorylation of KIT and its downstream effectors, and the increased global and gene-specific DNA methylation with the down-regulation of tumor suppressor gene epithelial cadherin CDH1...
July 24, 2015: Journal of Biological Chemistry
G Wedeh, S Cerny-Reiterer, G Eisenwort, H Herrmann, K Blatt, E Hadzijusufovic, I Sadovnik, L Müllauer, J Schwaab, T Hoffmann, J E Bradner, D Radia, W R Sperr, G Hoermann, A Reiter, H-P Horny, J Zuber, M Arock, P Valent
Advanced systemic mastocytosis (SM) is a life-threatening neoplasm characterized by uncontrolled growth and accumulation of neoplastic mast cells (MCs) in various organs and a poor survival. So far, no curative treatment concept has been developed for these patients. We identified the epigenetic reader bromodomain-containing protein-4 (BRD4) as novel drug target in aggressive SM (ASM) and MC leukemia (MCL). As assessed by immunohistochemistry and PCR, neoplastic MCs expressed substantial amounts of BRD4 in ASM and MCL...
November 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Zeenat Mirza, Hans-Juergen Schulten, Hasan Ma Farsi, Jaudah A Al-Maghrabi, Mamdooh A Gari, Adeel Ga Chaudhary, Adel M Abuzenadah, Mohammed H Al-Qahtani, Sajjad Karim
The S100A8 and epidermal growth factor receptor (EGFR) proteins are proto-oncogenes that are strongly expressed in a number of cancer types. EGFR promotes cellular proliferation, differentiation, migration and survival by activating molecular pathways. Involvement of proinflammatory S100A8 in tumor cell differentiation and progression is largely unclear and not studied in kidney cancer (KC). S100A8 and EGFR are potential therapeutic biomarkers and anticancer drug targets for KC. In this study, we explored molecular mechanisms of interaction profiles of both molecules with potential anticancer drugs...
2015: PloS One
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