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Richard Jove - One of the best experts on this subject based on the ideXlab platform.
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Dasatinib bms 354825 inhibits stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells
Molecular Cancer Therapeutics, 2007Co-Authors: Sangkil Nam, Francis Y Lee, Ann H Williams, Adina Vultur, Alan F List, Kapil N Bhalla, David D Smith, Richard JoveAbstract:Dasatinib (BMS-354825) is a novel, oral, potent, multi-targeted kinase inhibitor of Bcr-Abl and Src family kinases (SFK) and is a promising cancer therapeutic agent. Preclinical data indicate that Dasatinib is 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl, and that Dasatinib is active against 18 of 19 Bcr-Abl mutations known to cause imatinib resistance. Phase I clinical data show that Dasatinib is well tolerated and highly effective for the treatment of imatinib-resistant/imatinib-intolerant chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, the molecular mechanism of action of Dasatinib is not fully understood. In this study, we confirm that Dasatinib inhibits tyrosine phosphorylation of SFKs, including Src, Hck, and Lyn, in K562 human CML cells. Significantly, downstream signal transducer and activator of transcription 5 (Stat5) signaling is also blocked by Dasatinib as shown by decreases in levels of phosphorylated Stat5 and Stat5 DNA-binding activities. In addition, Dasatinib down-regulates expression of Stat5 target genes, including Bcl-x, Mcl-1, and cyclin D1. Consistent with these results, blockade of Stat5 signaling by Dasatinib is accompanied by inhibition of cell proliferation and induction of apoptosis. Surprisingly, Stat5 DNA-binding activities are enhanced with increasing cell density, which is associated with resistance to apoptosis by Dasatinib. Our findings indicate that inhibition of Stat5 signaling downstream of Bcr-Abl/SFKs contributes to the action of Dasatinib, and, conversely, that increasing cell density up-regulates Stat5 activation and confers resistance to Dasatinib. Moreover, the level of phosphorylated Stat5 in CML cells represents a mechanistically relevant biomarker for monitoring inhibition of Bcr-Abl signaling by Dasatinib in CML patients using convenient immunocytochemical assays.
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Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on src kinase for survival
Cancer Research, 2007Co-Authors: Audrey C Shor, Francis Y Lee, Elizabeth A Keschman, Carlos A Murocacho, Douglas G Letson, Jonathan C Trent, Jack W Pledger, Richard JoveAbstract:Sarcomas are rare malignant mesenchymal tumors for which there are limited treatment options. One potential molecular target for sarcoma treatment is the Src tyrosine kinase. Dasatinib (BMS-354825), a small-molecule inhibitor of Src kinase activity, is a promising cancer therapeutic agent with p.o. bioavailability. Dasatinib exhibits antitumor effects in cultured human cell lines derived from epithelial tumors, including prostate and lung carcinomas. However, the action of Dasatinib in mesenchymally derived tumors has yet to be shown. Based on our previous findings of Src activation in human sarcomas, we evaluated the effects of Dasatinib in 12 cultured human sarcoma cell lines derived from bone and soft tissue sarcomas. Dasatinib inhibited Src kinase activity at nanomolar concentrations in these sarcoma cell lines. Downstream components of Src signaling, including focal adhesion kinase and Crk-associated substrate (p130 CAS ), were also inhibited at similar concentrations. This inhibition of Src signaling was accompanied by blockade of cell migration and invasion. Moreover, apoptosis was induced in the osteosarcoma and Ewing9s subset of bone sarcomas at nanomolar concentrations of Dasatinib. Inhibition of Src protein expression by small interfering RNA also induced apoptosis, indicating that these bone sarcoma cell lines are dependent on Src activity for survival. These results show that Dasatinib inhibits migration and invasion of diverse sarcoma cell types and selectively blocks the survival of bone sarcoma cells. Therefore, Dasatinib may provide therapeutic benefit by preventing the growth and metastasis of sarcomas in patients. [Cancer Res 2007;67(6):2800–8]
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Dasatinib bms 354825 a novel multi targeted kinase inhibitor that blocks tumor cell migration and invasion is a promising therapeutic agent for metastatic prostate cancer
Cancer Research, 2006Co-Authors: Jin Q Cheng, Ralf Buettner, Janni Mirosevich, Shumin Zhang, Richard JoveAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 3797 SRC family kinases (SFKs) are currently being investigated as targets for treatment strategies in various cancers. Dasatinib (BMS-354825) is a novel, highly potent, oral, multi-targeted kinase inhibitor of BCR-ABL and SFKs. Dasatinib has been shown to inhibit growth of BCR-ABL-dependent chronic myeloid leukemia xenografts in nude mice and has been efficacious and well tolerated in a Phase I clinical trial of patients with imatinib-resistant or -intolerant CML. Dasatinib has also demonstrated activity against cultured human prostate and breast cancer cells; however, the molecular mechanism by which Dasatinib acts on epithelial tumor cells remains unknown. In this study, we show that Dasatinib blocks the kinase activities of the SFKs, Lyn and Src in human prostate cancer cells at low nanomolar concentrations. Moreover, focal adhesion kinase (FAK), which has been shown to be elevated in epithelial tumors, and Crk-associated substrate (p130CAS) signaling downstream of SFKs are also inhibited at similar Dasatinib concentrations. Consistent with inhibition of these signaling pathways, Dasatinib suppresses cell adhesion, migration, and invasion of prostate cancer cells at low nanomolar concentrations. Therefore, Dasatinib has potential as a therapeutic agent for metastatic prostate cancers harboring activated SFK and FAK signaling. Phase I clinical evaluation of Dasatinib in a variety of solid tumors, including prostate cancer, is currently ongoing.
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action of the src family kinase inhibitor Dasatinib bms 354825 on human prostate cancer cells
Cancer Research, 2005Co-Authors: Sangkil Nam, Donghwa Kim, Jin Q Cheng, Ralf Buettner, Janni Mirosevich, Francis Y Lee, Shumin M Zhang, Jihyun Lee, Richard JoveAbstract:Src family kinases (SFK) are currently being investigated as targets for treatment strategies in various cancers. The novel SFK/Abl inhibitor, Dasatinib (BMS-354825), is a promising therapeutic agent with oral bioavailability. Dasatinib has been shown to inhibit growth of Bcr-Abl–dependent chronic myeloid leukemia xenografts in nude mice. Dasatinib also has been shown to have activity against cultured human prostate and breast cancer cells. However, the molecular mechanism by which Dasatinib acts on epithelial tumor cells remains unknown. In this study, we show that Dasatinib blocks the kinase activities of the SFKs, Lyn, and Src, in human prostate cancer cells at low nanomolar concentrations. Moreover, focal adhesion kinase and Crk-associated substrate (p130CAS) signaling downstream of SFKs are also inhibited at similar concentrations of Dasatinib. Consistent with inhibition of these signaling pathways, Dasatinib suppresses cell adhesion, migration, and invasion of prostate cancer cells at low nanomolar concentrations. Therefore, Dasatinib has potential as a therapeutic agent for metastatic prostate cancers harboring activated SFK and focal adhesion kinase signaling.
Neil P Shah - One of the best experts on this subject based on the ideXlab platform.
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final 5 year study results of dasision the Dasatinib versus imatinib study in treatment naive chronic myeloid leukemia patients trial
Journal of Clinical Oncology, 2016Co-Authors: Jorge E Cortes, Neil P Shah, Giuseppe Saglio, Hagop M Kantarjian, Michele Baccarani, Jiři Mayer, Concepcion Boque, Charles Chuah, Luis Casanova, Brigid BradleygarelikAbstract:PurposeWe report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with Dasatinib or imatinib.Patients and MethodsPatients with newly diagnosed CML-CP were randomly assigned to receive Dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260).ResultsAt the time of study closure, 61% and 63% of Dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for Dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatin...
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early response with Dasatinib or imatinib in chronic myeloid leukemia 3 year follow up from a randomized phase 3 trial dasision
Blood, 2014Co-Authors: Elias J Jabbour, Neil P Shah, Giuseppe Saglio, Hagop M Kantarjian, Jiři Mayer, Concepcion Boque, Charles Chuah, Juan Luis Steegmann, Carolina Pavlovsky, Jorge E CortesAbstract:This analysis explores the impact of early cytogenetic and molecular responses on the outcomes of patients with chronic myeloid leukemia in chronic phase (CML-CP) in the phase 3 Dasatinib versus Imatinib Study In treatment-Naive CML patients trial with a minimum follow-up of 3 years. Patients with newly diagnosed CML-CP were randomized to receive 100 mg Dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. The retrospective landmark analysis included patients evaluable at the relevant time point (3, 6, or 12 months). Median time to complete cytogenetic response was 3 vs 6 months with Dasatinib vs imatinib. At 3 and 6 months, the proportion of patients with BCR-ABL transcript levels ≤10% was higher in the Dasatinib arm. Deeper responses at 3, 6, and 12 months were observed in a higher proportion of patients on Dasatinib therapy and were associated with better 3-year progression-free survival and overall survival in both arms. First-line Dasatinib resulted in faster and deeper responses compared with imatinib. The achievement of an early molecular response was predictive of improved progression-free survival and overall survival, supporting new milestones for optimal response in patients with early CML-CP treated with tyrosine kinase inhibitors. This study was registered at www.clinicaltrials.gov as NCT00481247.
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differential effects of dosing regimen on the safety and efficacy of Dasatinib retrospective exposure response analysis of a phase iii study
Clinical Pharmacology: Advances and Applications, 2013Co-Authors: Xiaoning Wang, Hagop M Kantarjian, A Hochhaus, Amit Roy, Taitsang Chen, Neil P ShahAbstract:Purpose Dasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of Dasatinib for chronic myeloid leukemia in chronic phase was changed from 70 mg twice daily to 100 mg once daily following a Phase III dose-optimization study. To better understand the superior benefit–risk profile of Dasatinib 100 mg once daily, exposure–response was characterized for efficacy (major cytogenetic response) and safety (pleural effusion).
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Dasatinib or imatinib in newly diagnosed chronic phase chronic myeloid leukemia 2 year follow up from a randomized phase 3 trial dasision
Blood, 2012Co-Authors: Hagop M Kantarjian, Neil P Shah, Jorge E Cortes, Michele Baccarani, Mohan B Agarwal, Maria Soledad Undurraga, Jianxiang Wang, Juan Julio Kassack Ipina, Dongwook Kim, Michinori OguraAbstract:Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive Dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for Dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in Dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with Dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with Dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with Dasatinib. Overall, Dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of Dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.
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lymphocytosis following first line treatment for cml in chronic phase with Dasatinib is associated with improved responses a comparison with imatinib
Blood, 2010Co-Authors: Charles A Schiffer, Francois Guilhot, Philipp Le Coutre, Erkut Bahceci, David Dejardin, Giuseppe Saglio, Neil P ShahAbstract:Abstract 358 Background: Persistent expansion of clonal cytotoxic T cells or NK cells has been described in patients with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) receiving Dasatinib. These small studies have suggested a relationship between the development of T/NK lymphocytosis with both toxicity and improved response. A recent analysis of CML patients who were resistant to or intolerant of imatinib indicated that lymphocytosis occurs in ∼30% of patients in all stages of CML after treatment with Dasatinib (Schiffer 2010 ASCO abstract #6553). In addition, lymphocytosis was associated with improved cytogenetic response and an increased incidence of pleural effusions. The DASISION study (CA180-056) compared Dasatinib with imatinib in patients with newly diagnosed, previously untreated chronic phase CML. This subanalysis of the DASISION data was undertaken to determine the safety profile, responses, and outcomes in those patients with sustained lymphocytosis. Method: Patients enrolled in the DASISION study were retrospectively evaluated for lymphocytosis (N=516). Lymphocytosis was defined as lymphocytes >3.6 × 10 9 /L on ≥2 occasions after 28 days of treatment. Immunophenotyping was not done as part of these studies. Rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were measured in those with and without lymphocytosis. The median follow-up was 14.0 and 14.3 months for Dasatinib and imatinib, respectively. Result: Lymphocytosis occurred more frequently and sooner in patients treated with Dasatinib compared with imatinib (23.6% vs 5.4% and 3.0 months vs 4.7 months, respectively). Dasatinib-treated patients who developed lymphocytosis had lower baseline Hasford risk scores, whereas imatinib-treated patients who developed lymphocytosis had high Hasford risk scores. In the presence or absence of lymphocytosis, MCyR and CCyR occurred more frequently with Dasatinib as compared with imatinib. In Dasatinib treated patients, lymphocytosis was associated with a higher MCyR rate (91.8% with vs 83.3% without) and CCyR rate (83.6% with vs 75.1% without). In imatinib-treated patients, lymphocytosis was associated with a lower MCyR rate (50.0% with vs 82.8% without) and CCyR rate (50.0% with vs 69.7% without). Patients with lymphocytosis, compared with those without it, had higher rates of pleural effusion (any grade) on Dasatinib (18.0% vs 7.6%, respectively). Only 1 patient treated with imatinib, who did not have lymphocytosis, experienced pleural effusion. Dasatinib-treated patients with lymphocytosis, compared with those without it, had higher rates of fatigue (16.4% vs 9.1%,); this trend was reversed for imatinib-treated patients (7.1% vs 11.9%). Patients with lymphocytosis, compared with those without it had lower rates of myalgias and arthralgias (all grades) on both the Dasatinib arm (11.5% vs 18.8%) and the imatinib arm (7.1% vs 24.2%). Conclusion: Lymphocytosis occurred much more frequently and sooner in patients treated with Dasatinib than with imatinib. Lymphocytosis was associated with improved responses (MCyR and CCyR) in Dasatinib-treated patients. An apparent inverse relationship was observed in imatinib-treated patients, although the number of patients with lymphocytosis was small. It remains to be determined how lymphocytosis, baseline Hasford risk score, and response are correlated. It is possible that some of the antileukemic effects of Dasatinib are produced by an immunomodulatory mechanism. Lymphocytosis in Dasatinib-treated patients was associated with an increased rate of pleural effusion and a possible decrease in myalgias and arthralgias. Longer follow-up is needed to assess whether lymphocytosis has an effect on PFS. Disclosures: Schiffer: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Cellgenix: Consultancy; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Cortes: Bristol-Myers Squibb: Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. le Coutre: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Guilhot: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Bahceci: Bristol-Myers Squibb: Employment. Dejardin: Bristol-Myers Squibb: Employment. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy.
Francis Y Lee - One of the best experts on this subject based on the ideXlab platform.
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activities of syk and plcγ2 predict apoptotic response of cll cells to src tyrosine kinase inhibitor Dasatinib
Clinical Cancer Research, 2010Co-Authors: Zibo Song, Francis Y Lee, Richard R Furman, John P Leonard, Peter Martin, Lauren Tyrell, Daniel M Knowles, Morton Coleman, Lynn Y WangAbstract:Purpose: B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with Dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential Dasatinib sensitivity and to uncover more effective therapeutic targets in CLL. Experimental Design: Fresh CLL B cells were treated with Dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors. Results: Among 50 CLL cases, Dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by Dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cγ2, correlate well with the apoptotic response of CLL cells to Dasatinib. Conclusions: Thus, SYK inhibition predicts cellular response to Dasatinib. SYK, together with phospholipase Cγ2, may serve as potential biomarkers to predict Dasatinib therapeutic response in patients. From the pathogenic perspective, our study suggests the existence of alternative mechanisms or pathways that activate SYK, independent of SRC kinase activities. The study further implicates that SYK might serve as a more effective therapeutic target in CLL treatment. Clin Cancer Res; 16(2); 587–99
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metabolism and disposition of Dasatinib after oral administration to humans
Drug Metabolism and Disposition, 2008Co-Authors: Lisa J Christopher, Michael W Lago, Francis Y Lee, James Manning, Roger T Luo, Donghui Cui, Samuel J Bonacorsi, Alban Allentoff, Betty Mccann, Susan GalbraithAbstract:SPRYCEL (Dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]Dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both Dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h. Dasatinib was the major drug-related component in human plasma. At 2 h, Dasatinib accounted for 25% of the TRA in plasma, suggesting that metabolites contributed significantly to the total drug-related component. There were many circulating metabolites detected that included hydroxylated metabolites (M20 and M24), an N-dealkylated metabolite (M4), an N-oxide (M5), an acid metabolite (M6), glucuronide conjugates (M8a,b), and products of further metabolism of these primary metabolites. Most of the administered radioactivity was eliminated in the feces (85%). Urine recovery accounted for <4% of the dose. Dasatinib accounted for <1 and 19% of the dose in urine and feces, respectively, suggesting that Dasatinib was well absorbed after p.o. administration and extensively metabolized before being eliminated from the body. The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC(50) for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.
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preclinical pharmacokinetics and in vitro metabolism of Dasatinib bms 354825 a potent oral multi targeted kinase inhibitor against src and bcr abl
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Amrita V Kamath, Francis Y Lee, Jian Wang, Punit MaratheAbstract:Purpose Dasatinib (BMS-354825), a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL, has recently been approved for the treatment of chronic myelogenous leukaemia (CML) in imatinib-acquired resistance and intolerance. In vitro and in vivo studies were conducted to characterize the pharmacokinetics and metabolism of Dasatinib in mouse, rat, dog, and monkey. Possible mechanisms contributing to the incomplete oral bioavailability of Dasatinib in animals were investigated.
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Dasatinib bms 354825 inhibits stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells
Molecular Cancer Therapeutics, 2007Co-Authors: Sangkil Nam, Francis Y Lee, Ann H Williams, Adina Vultur, Alan F List, Kapil N Bhalla, David D Smith, Richard JoveAbstract:Dasatinib (BMS-354825) is a novel, oral, potent, multi-targeted kinase inhibitor of Bcr-Abl and Src family kinases (SFK) and is a promising cancer therapeutic agent. Preclinical data indicate that Dasatinib is 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl, and that Dasatinib is active against 18 of 19 Bcr-Abl mutations known to cause imatinib resistance. Phase I clinical data show that Dasatinib is well tolerated and highly effective for the treatment of imatinib-resistant/imatinib-intolerant chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, the molecular mechanism of action of Dasatinib is not fully understood. In this study, we confirm that Dasatinib inhibits tyrosine phosphorylation of SFKs, including Src, Hck, and Lyn, in K562 human CML cells. Significantly, downstream signal transducer and activator of transcription 5 (Stat5) signaling is also blocked by Dasatinib as shown by decreases in levels of phosphorylated Stat5 and Stat5 DNA-binding activities. In addition, Dasatinib down-regulates expression of Stat5 target genes, including Bcl-x, Mcl-1, and cyclin D1. Consistent with these results, blockade of Stat5 signaling by Dasatinib is accompanied by inhibition of cell proliferation and induction of apoptosis. Surprisingly, Stat5 DNA-binding activities are enhanced with increasing cell density, which is associated with resistance to apoptosis by Dasatinib. Our findings indicate that inhibition of Stat5 signaling downstream of Bcr-Abl/SFKs contributes to the action of Dasatinib, and, conversely, that increasing cell density up-regulates Stat5 activation and confers resistance to Dasatinib. Moreover, the level of phosphorylated Stat5 in CML cells represents a mechanistically relevant biomarker for monitoring inhibition of Bcr-Abl signaling by Dasatinib in CML patients using convenient immunocytochemical assays.
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Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on src kinase for survival
Cancer Research, 2007Co-Authors: Audrey C Shor, Francis Y Lee, Elizabeth A Keschman, Carlos A Murocacho, Douglas G Letson, Jonathan C Trent, Jack W Pledger, Richard JoveAbstract:Sarcomas are rare malignant mesenchymal tumors for which there are limited treatment options. One potential molecular target for sarcoma treatment is the Src tyrosine kinase. Dasatinib (BMS-354825), a small-molecule inhibitor of Src kinase activity, is a promising cancer therapeutic agent with p.o. bioavailability. Dasatinib exhibits antitumor effects in cultured human cell lines derived from epithelial tumors, including prostate and lung carcinomas. However, the action of Dasatinib in mesenchymally derived tumors has yet to be shown. Based on our previous findings of Src activation in human sarcomas, we evaluated the effects of Dasatinib in 12 cultured human sarcoma cell lines derived from bone and soft tissue sarcomas. Dasatinib inhibited Src kinase activity at nanomolar concentrations in these sarcoma cell lines. Downstream components of Src signaling, including focal adhesion kinase and Crk-associated substrate (p130 CAS ), were also inhibited at similar concentrations. This inhibition of Src signaling was accompanied by blockade of cell migration and invasion. Moreover, apoptosis was induced in the osteosarcoma and Ewing9s subset of bone sarcomas at nanomolar concentrations of Dasatinib. Inhibition of Src protein expression by small interfering RNA also induced apoptosis, indicating that these bone sarcoma cell lines are dependent on Src activity for survival. These results show that Dasatinib inhibits migration and invasion of diverse sarcoma cell types and selectively blocks the survival of bone sarcoma cells. Therefore, Dasatinib may provide therapeutic benefit by preventing the growth and metastasis of sarcomas in patients. [Cancer Res 2007;67(6):2800–8]
Hagop M Kantarjian - One of the best experts on this subject based on the ideXlab platform.
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a propensity score matching analysis of Dasatinib and nilotinib as a frontline therapy for patients with chronic myeloid leukemia in chronic phase
Cancer, 2016Co-Authors: Koichi Takahashi, Hagop M Kantarjian, Farhad Ravandi, Yulong Yang, Koji Sasaki, Preetesh Jain, Sara Dellasala, Tapan M Kadia, Naveen Pemmaraju, Naval DaverAbstract:BACKGROUND Both Dasatinib and nilotinib are approved frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) based on randomized trials compared with imatinib. However, no head-to-head comparison of Dasatinib and nilotinib has been conducted in patients with newly diagnosed CML-CP. METHODS The authors conducted a propensity score (PS) matched comparison of patients with CML-CP who received frontline therapy with either Dasatinib (N = 102) or nilotinib (N = 104) under the respective phase 2 trials conducted in parallel. RESULTS PS matching resulted in 87 patients from each trial being matched for pretreatment characteristics. The 3-month BCR-ABL1/ABL1 ratio <10% rate was 93% with Dasatinib and 94% with nilotinib (P = .25); the rates of major molecular response at 12 months were 77% and 85%, respectively (P = .13); and the rates of molecular response with 4.5-log reduction in the ratio at 36 months were 66% and 64%, respectively (P = .96). All other clinically relevant responses were similar between the 2 treatment cohorts. The 3-year probability of event-free survival was 89% among the patients who received Dasatinib and 87% among those who received nilotinib (P = .99), and the corresponding 3-year overall survival probabilities were 99% and 93%, respectively (P = .95). No statistical difference was observed between the Dasatinib and nilotinib groups in any of the other survival endpoints. The treatment discontinuation rate also was similar between the 2 cohorts (Dasatinib group, 18%; nilotinib group, 19%; P = .82). CONCLUSIONS In a PS-matched cohort of patients with newly diagnosed CML-CP, Dasatinib and nilotinib offer similar response and survival outcomes. Both drugs can be considered reasonable standard-of-care options as first-line therapy for patients with CML-CP. Cancer 2016;122:3336–3343. © 2016 American Cancer Society.
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final 5 year study results of dasision the Dasatinib versus imatinib study in treatment naive chronic myeloid leukemia patients trial
Journal of Clinical Oncology, 2016Co-Authors: Jorge E Cortes, Neil P Shah, Giuseppe Saglio, Hagop M Kantarjian, Michele Baccarani, Jiři Mayer, Concepcion Boque, Charles Chuah, Luis Casanova, Brigid BradleygarelikAbstract:PurposeWe report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with Dasatinib or imatinib.Patients and MethodsPatients with newly diagnosed CML-CP were randomly assigned to receive Dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260).ResultsAt the time of study closure, 61% and 63% of Dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for Dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatin...
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early response with Dasatinib or imatinib in chronic myeloid leukemia 3 year follow up from a randomized phase 3 trial dasision
Blood, 2014Co-Authors: Elias J Jabbour, Neil P Shah, Giuseppe Saglio, Hagop M Kantarjian, Jiři Mayer, Concepcion Boque, Charles Chuah, Juan Luis Steegmann, Carolina Pavlovsky, Jorge E CortesAbstract:This analysis explores the impact of early cytogenetic and molecular responses on the outcomes of patients with chronic myeloid leukemia in chronic phase (CML-CP) in the phase 3 Dasatinib versus Imatinib Study In treatment-Naive CML patients trial with a minimum follow-up of 3 years. Patients with newly diagnosed CML-CP were randomized to receive 100 mg Dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. The retrospective landmark analysis included patients evaluable at the relevant time point (3, 6, or 12 months). Median time to complete cytogenetic response was 3 vs 6 months with Dasatinib vs imatinib. At 3 and 6 months, the proportion of patients with BCR-ABL transcript levels ≤10% was higher in the Dasatinib arm. Deeper responses at 3, 6, and 12 months were observed in a higher proportion of patients on Dasatinib therapy and were associated with better 3-year progression-free survival and overall survival in both arms. First-line Dasatinib resulted in faster and deeper responses compared with imatinib. The achievement of an early molecular response was predictive of improved progression-free survival and overall survival, supporting new milestones for optimal response in patients with early CML-CP treated with tyrosine kinase inhibitors. This study was registered at www.clinicaltrials.gov as NCT00481247.
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differential effects of dosing regimen on the safety and efficacy of Dasatinib retrospective exposure response analysis of a phase iii study
Clinical Pharmacology: Advances and Applications, 2013Co-Authors: Xiaoning Wang, Hagop M Kantarjian, A Hochhaus, Amit Roy, Taitsang Chen, Neil P ShahAbstract:Purpose Dasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of Dasatinib for chronic myeloid leukemia in chronic phase was changed from 70 mg twice daily to 100 mg once daily following a Phase III dose-optimization study. To better understand the superior benefit–risk profile of Dasatinib 100 mg once daily, exposure–response was characterized for efficacy (major cytogenetic response) and safety (pleural effusion).
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Dasatinib or imatinib in newly diagnosed chronic phase chronic myeloid leukemia 2 year follow up from a randomized phase 3 trial dasision
Blood, 2012Co-Authors: Hagop M Kantarjian, Neil P Shah, Jorge E Cortes, Michele Baccarani, Mohan B Agarwal, Maria Soledad Undurraga, Jianxiang Wang, Juan Julio Kassack Ipina, Dongwook Kim, Michinori OguraAbstract:Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive Dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for Dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in Dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with Dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with Dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with Dasatinib. Overall, Dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of Dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.
Daniel J Deangelo - One of the best experts on this subject based on the ideXlab platform.
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one year and long term molecular response to nilotinib and Dasatinib for newly diagnosed chronic myeloid leukemia a matching adjusted indirect comparison
Current Medical Research and Opinion, 2015Co-Authors: James Signorovitch, Lei Chen, Keith A Betts, William M Reichmann, Darren Thomason, Phil Galebach, Daniel J DeangeloAbstract:AbstractBackground:Nilotinib and Dasatinib have shown superior rates of molecular response (MR) compared to imatinib for the treatment of newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP). This study indirectly compares MR in patients taking nilotinib 300 mg bid with that in those taking Dasatinib 100 mg qd by 12 months and through 48 months.Methods:Patients in ENESTnd were re-weighted to match published baseline characteristics reported for DASISION using a propensity score model. After matching, differences in rates of major MR (MMR, measured as a 3 log reduction on the International Scale [IS]), MR4.0 (4 log reduction on IS), and MR4.5 (4.5 log reduction on IS) relative to imatinib were indirectly compared between nilotinib and Dasatinib. Hazard ratios (HRs) were used to indirectly compare MR outcomes between nilotinib and Dasatinib through 48 months of follow-up, while rate differences were used to compare progression to AP/BC between nilotinib and Dasatinib by 48 months.Results:Aft...
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comparative efficacy of nilotinib and Dasatinib in newly diagnosed chronic myeloid leukemia a matching adjusted indirect comparison of randomized trials
Current Medical Research and Opinion, 2011Co-Authors: James Signorovitch, Keith A Betts, Kejal Parikh, Evan Kantor, Amy Guo, Vamsi Bollu, Denise Williams, L J Wei, Daniel J DeangeloAbstract:AbstractObjective:Nilotinib and Dasatinib have not been directly compared in a randomized trial for the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP). The purpose of this study was to indirectly compare rates of major molecular response (MMR), progression-free survival (PFS) and overall survival by month 12 with nilotinib and Dasatinib treatment of newly diagnosed CML-CP.Methods:Individual patient data from a randomized trial of nilotinib vs. imatinib (ENESTnd) and published summary data from a separate randomized trial of Dasatinib vs. imatinib (DASISION) were utilized. A matching-adjusted indirect comparison was conducted by weighting individual patients treated with nilotinib to match baseline characteristics reported for Dasatinib-treated patients, including age, gender, ECOG performance status and hematology lab values. After matching, efficacy outcomes were compared for patients treated with nilotinib 300 mg twice daily vs. Dasatinib 100 mg once daily. Patients ...
