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Hagop M Kantarjian - One of the best experts on this subject based on the ideXlab platform.
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phase 1 study of inno 406 a dual abl lyn kinase inhibitor in philadelphia chromosome positive leukemias after Imatinib Resistance or intolerance
Cancer, 2010Co-Authors: Hagop M Kantarjian, Jorge E. Cortes, Andreas Hochhaus, Phillipp Le D Coutre, Javier Pinillaibarz, Arnon Nagler, Shinya Kimura, Oliver G OttmannAbstract:BACKGROUND: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after Imatinib Resistance or intolerance. METHODS: A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. RESULTS: INNO-406 was administered to 56 patients with Imatinib Resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia. CONCLUSIONS: INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored. Cancer 2010. © 2010 American Cancer Society.
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predictors of primary Imatinib Resistance in chronic myelogenous leukemia are distinct from those in secondary Imatinib Resistance
Journal of Clinical Oncology, 2009Co-Authors: Wenyong Zhang, Jorge E. Cortes, Hagop M Kantarjian, Elias Jabbour, Hui Yao, Li Zhang, Neelima Reddy, Dan JonesAbstract:Purpose A subset of patients with chronic myelogenous leukemia (CML) do not respond to the tyrosine kinase inhibitor (TKI) Imatinib mesylate. Such primary Imatinib Resistance is distinguished from secondary Resistance which reemerges after attainment of cytogenetic remission. Patients and Methods We studied gene expression patterns in total WBCs using a panel of 21 genes previously implicated in TKI handling, Resistance, or progression comparing patients who had newly diagnosed TKI-naive CML that had optimal (n = 41), or suboptimal (n = 7) responses to Imatinib, or primary Resistance (n = 20). Expression patterns were compared to those in secondary TKI-resistant chronic phase CML without ABL1 kinase domain mutations (n = 29), and to lymphoid (n = 15) or myeloid blast phase disease (n = 12). Results Fifteen genes in the panel distinguished blast phase from chronic phase disease, and 12 genes distinguished newly diagnosed CML from TKI-resistant CML without ABL1 kinase domain mutations, but only a single gen...
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mechanisms of primary and secondary Resistance to Imatinib in chronic myeloid leukemia
Cancer Control, 2009Co-Authors: Alfonso Quintascardama, Hagop M Kantarjian, Jorge E. CortesAbstract:Background: Although the vast majority of patients with chronic myeloid leukemia (CML) respond to the tyrosine kinase inhibitor (TKI) Imatinib mesylate, Resistance might occur de novo or during treatment. Methods: The authors reviewed the known mechanisms of primary and secondary Resistance to Imatinib and other TKIs used in the management of CML. Results: Mutations within the kinase domain of BCR-ABLI account for 30% to 40% of cases of Imatinib Resistance. Other mechanisms include BCR-ABLI amplification, overexpression of the SRC family of kinases, and pharmacokinetic and pharmacodynamic factors. Conclusions: Although not all Resistance mechanisms have been identified and understood, several agents based on the known mechanisms have alrea dy been designed and developed and are beginning clinical trials. Several factors are associated with Imatinib Resistance, and some interventions have already been designed to reverse this clinical problem.
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bcr abl alternative splicing as a common mechanism for Imatinib Resistance evidence from molecular dynamics simulations
Molecular Cancer Therapeutics, 2008Co-Authors: Taisung Lee, Jorge E. Cortes, Hagop M Kantarjian, Francis J Giles, Xi Zhang, Maher AlbitarAbstract:Rare cases of chronic myelogenous leukemia (CML) express high levels of alternatively spliced BCR-ABL mRNA with a 35-bp insertion (35INS) between ABL kinase domain exons 8 and 9. This insertion results in a frameshift leading to the addition of 10 residues and truncation of 653 residues due to early termination. Sensitive PCR-based testing showed that 32 of 52 (62%) Imatinib-resistant CML patients in chronic phase and 8 of 38 (21%) in accelerated or blast crisis expressed varying levels of the alternatively spliced BCR-ABL mRNA. A three-dimensional structural model of the 35INS ABL kinase domain complexed with Imatinib was built using homology modeling, followed by molecular dynamics simulations. Simulation results showed that the new residues cause a significant global conformational change, altering Imatinib binding in a way similar to that of the T315I mutation and, therefore, providing Resistance to Imatinib that depends on the level of expression.
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molecular basis explanation for Imatinib Resistance of bcr abl due to t315i and p loop mutations from molecular dynamics simulations
Cancer, 2008Co-Authors: Taisung Lee, Jorge E. Cortes, Hagop M Kantarjian, Francis J Giles, Steven J Potts, Maher AlbitarAbstract:BACKGROUND Computational simulations have become powerful tools for understanding detailed interactions in biologic systems. To the authors' knowledge to date, the mechanism of Imatinib Resistance in BCR-ABL has not been clarified at the atomic level, and computational studies are required. METHODS Molecular dynamics (MD) simulations on the complex of Imatinib with the wild-type, T315I mutant, and 10 other P-loop mutants of the tyrosine kinase BCR-ABL were performed to study the mechanism of Imatinib Resistance. RESULTS Simulations suggested that Imatinib Resistance of T315I results mainly comes from the breakdown of interactions between Imatinib and both E286 and M290, contradictory to what was believed previously, in that the missing hydrogen bonding is the main contribution. The current results also demonstrated that the unfavorable electrostatic interaction between P-loop and Imatinib is the main reason for Resistance for the P-loop mutations. Furthermore, in Y253H, protonation of the histidine at the e position is essential for rendering this mutation resistant to Imatinib. CONCLUSIONS The current results indicated that large-scale simulations may offer insight and information that other simple modeling methods cannot provide regarding the problem of BCR-ABL Imatinib Resistance, especially in the case of conformational changes because of remote mutations. Imatinib Resistance mechanisms that were not anticipated previously were revealed by analyzing the interactions between Imatinib and individual residues based on simulation results. This results demonstrated that MD is a powerful way to verify and predict the clinical response or Resistance to Imatinib and to other potential drugs. Cancer 2008. © 2008 American Cancer Society.
Jorge E. Cortes - One of the best experts on this subject based on the ideXlab platform.
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nilotinib in patients with ph chronic myeloid leukemia in accelerated phase following Imatinib Resistance or intolerance 24 month follow up results
Leukemia, 2012Co-Authors: Le P Coutre, Francis J Giles, Andreas Hochhaus, Jane F Apperley, G J Ossenkoppele, Rick E Blakesley, Yaping Shou, Neil Gallagher, Michele Baccarani, Jorge E. CortesAbstract:Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following Imatinib Resistance or intolerance: 24-month follow-up results
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epigenetic therapy with hydralazine and magnesium valproate reverses Imatinib Resistance in patients with chronic myeloid leukemia
Clinical Lymphoma Myeloma & Leukemia, 2012Co-Authors: Eduardo Cervera, Jorge E. Cortes, Myrna Candelaria, Omar Lopeznavarro, Juan Labardini, Aurora Gonzalezfierro, Lucia Tajachayeb, Daniela Gordillobastidas, Alfonso DuenasgonzalezAbstract:Abstract Background Epigenetic alterations participate in the development of acquired Resistance to Imatinib, hence, the DNA methylation, and histone deacetylase inhibitors hydralazine and valproate, respectively, has the potential to overcome it. Patient and Methods A series of 8 patients with chronic myeloid leukemia (CML) refractory to Imatinib mesylate with no access to second-generation tyrosine kinase inhibitors were treated with hydralazine and valproate in a compassionate manner. Clinical efficacy and safety of these drugs added to Imatinib mesylate were evaluated. Results Two patients were in the blast phase, 5 were in the accelerated phase, and 1 was in the chronic phase. All the patients continued with the same dose of Imatinib that they had been receiving at the time of development of Resistance, with a median dose of 600 mg daily (range, 400-800 mg). The median time from diagnosis of CML to the start of hydralazine and valproate was 53.6 months (range, 19-84 months). Two (25%) patients had a complete hematologic response, one (12.5%) had an major cytogenetic response, and one (12.5%) had a complete cytogenetic response. Three (37.5%) patients had stable disease, and only one (12.5%) patient failed to respond. At a median follow-up time of 18 months (range, 3-18 months), the median survival had not been reached, and the projected overall survival was 63%. All the patients had mild neurologic toxicity, including distal tremor and somnolence. No grade 3 or 4 toxicity was observed. Conclusions Our results suggest that the epigenetic drugs hydralazine and valproate revert the Resistance to Imatinib in patients with CML.
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phase 1 study of inno 406 a dual abl lyn kinase inhibitor in philadelphia chromosome positive leukemias after Imatinib Resistance or intolerance
Cancer, 2010Co-Authors: Hagop M Kantarjian, Jorge E. Cortes, Andreas Hochhaus, Phillipp Le D Coutre, Javier Pinillaibarz, Arnon Nagler, Shinya Kimura, Oliver G OttmannAbstract:BACKGROUND: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after Imatinib Resistance or intolerance. METHODS: A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. RESULTS: INNO-406 was administered to 56 patients with Imatinib Resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia. CONCLUSIONS: INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored. Cancer 2010. © 2010 American Cancer Society.
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predictors of primary Imatinib Resistance in chronic myelogenous leukemia are distinct from those in secondary Imatinib Resistance
Journal of Clinical Oncology, 2009Co-Authors: Wenyong Zhang, Jorge E. Cortes, Hagop M Kantarjian, Elias Jabbour, Hui Yao, Li Zhang, Neelima Reddy, Dan JonesAbstract:Purpose A subset of patients with chronic myelogenous leukemia (CML) do not respond to the tyrosine kinase inhibitor (TKI) Imatinib mesylate. Such primary Imatinib Resistance is distinguished from secondary Resistance which reemerges after attainment of cytogenetic remission. Patients and Methods We studied gene expression patterns in total WBCs using a panel of 21 genes previously implicated in TKI handling, Resistance, or progression comparing patients who had newly diagnosed TKI-naive CML that had optimal (n = 41), or suboptimal (n = 7) responses to Imatinib, or primary Resistance (n = 20). Expression patterns were compared to those in secondary TKI-resistant chronic phase CML without ABL1 kinase domain mutations (n = 29), and to lymphoid (n = 15) or myeloid blast phase disease (n = 12). Results Fifteen genes in the panel distinguished blast phase from chronic phase disease, and 12 genes distinguished newly diagnosed CML from TKI-resistant CML without ABL1 kinase domain mutations, but only a single gen...
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mechanisms of primary and secondary Resistance to Imatinib in chronic myeloid leukemia
Cancer Control, 2009Co-Authors: Alfonso Quintascardama, Hagop M Kantarjian, Jorge E. CortesAbstract:Background: Although the vast majority of patients with chronic myeloid leukemia (CML) respond to the tyrosine kinase inhibitor (TKI) Imatinib mesylate, Resistance might occur de novo or during treatment. Methods: The authors reviewed the known mechanisms of primary and secondary Resistance to Imatinib and other TKIs used in the management of CML. Results: Mutations within the kinase domain of BCR-ABLI account for 30% to 40% of cases of Imatinib Resistance. Other mechanisms include BCR-ABLI amplification, overexpression of the SRC family of kinases, and pharmacokinetic and pharmacodynamic factors. Conclusions: Although not all Resistance mechanisms have been identified and understood, several agents based on the known mechanisms have alrea dy been designed and developed and are beginning clinical trials. Several factors are associated with Imatinib Resistance, and some interventions have already been designed to reverse this clinical problem.
Francis J Giles - One of the best experts on this subject based on the ideXlab platform.
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nilotinib in Imatinib resistant or Imatinib intolerant patients with chronic myeloid leukemia in chronic phase 48 month follow up results of a phase ii study
Leukemia, 2013Co-Authors: Francis J Giles, Norbert Gattermann, Andreas Hochhaus, Le P Coutre, Javier Pinillaibarz, Oliver G Ottmann, Richard A Larson, Giuseppe Saglio, J Radich, Timothy P HughesAbstract:Nilotinib (Tasigna) is a BCR–ABL1 tyrosine kinase inhibitor approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) who are newly diagnosed or intolerant of or resistant to Imatinib. The 48-month follow-up data for patients with CML-CP treated with nilotinib after Imatinib Resistance or intolerance on an international phase II study were analyzed. Overall, 59% of patients achieved major cytogenetic response; 45% achieved complete cytogenetic response while on study. The estimated rate of overall survival (OS) and progression-free survival (PFS) at 48 months was 78% and 57%, respectively. Deeper levels of molecular responses at 3 and 6 months were highly positively correlated with long-term outcomes, including PFS and OS at 48 months. Of the 321 patients initially enrolled in the study, 98 (31%) were treated for at least 48 months. Discontinuations were primarily due to disease progression (30%) or adverse events (21%). Nilotinib is safe and effective for long-term use in responding patients with CML-CP who are intolerant of or resistant to Imatinib. Further significant improvements in therapy are required for patients who are resistant or intolerant to Imatinib.
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nilotinib in patients with ph chronic myeloid leukemia in accelerated phase following Imatinib Resistance or intolerance 24 month follow up results
Leukemia, 2012Co-Authors: Le P Coutre, Francis J Giles, Andreas Hochhaus, Jane F Apperley, G J Ossenkoppele, Rick E Blakesley, Yaping Shou, Neil Gallagher, Michele Baccarani, Jorge E. CortesAbstract:Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following Imatinib Resistance or intolerance: 24-month follow-up results
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bcr abl alternative splicing as a common mechanism for Imatinib Resistance evidence from molecular dynamics simulations
Molecular Cancer Therapeutics, 2008Co-Authors: Taisung Lee, Jorge E. Cortes, Hagop M Kantarjian, Francis J Giles, Xi Zhang, Maher AlbitarAbstract:Rare cases of chronic myelogenous leukemia (CML) express high levels of alternatively spliced BCR-ABL mRNA with a 35-bp insertion (35INS) between ABL kinase domain exons 8 and 9. This insertion results in a frameshift leading to the addition of 10 residues and truncation of 653 residues due to early termination. Sensitive PCR-based testing showed that 32 of 52 (62%) Imatinib-resistant CML patients in chronic phase and 8 of 38 (21%) in accelerated or blast crisis expressed varying levels of the alternatively spliced BCR-ABL mRNA. A three-dimensional structural model of the 35INS ABL kinase domain complexed with Imatinib was built using homology modeling, followed by molecular dynamics simulations. Simulation results showed that the new residues cause a significant global conformational change, altering Imatinib binding in a way similar to that of the T315I mutation and, therefore, providing Resistance to Imatinib that depends on the level of expression.
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molecular basis explanation for Imatinib Resistance of bcr abl due to t315i and p loop mutations from molecular dynamics simulations
Cancer, 2008Co-Authors: Taisung Lee, Jorge E. Cortes, Hagop M Kantarjian, Francis J Giles, Steven J Potts, Maher AlbitarAbstract:BACKGROUND Computational simulations have become powerful tools for understanding detailed interactions in biologic systems. To the authors' knowledge to date, the mechanism of Imatinib Resistance in BCR-ABL has not been clarified at the atomic level, and computational studies are required. METHODS Molecular dynamics (MD) simulations on the complex of Imatinib with the wild-type, T315I mutant, and 10 other P-loop mutants of the tyrosine kinase BCR-ABL were performed to study the mechanism of Imatinib Resistance. RESULTS Simulations suggested that Imatinib Resistance of T315I results mainly comes from the breakdown of interactions between Imatinib and both E286 and M290, contradictory to what was believed previously, in that the missing hydrogen bonding is the main contribution. The current results also demonstrated that the unfavorable electrostatic interaction between P-loop and Imatinib is the main reason for Resistance for the P-loop mutations. Furthermore, in Y253H, protonation of the histidine at the e position is essential for rendering this mutation resistant to Imatinib. CONCLUSIONS The current results indicated that large-scale simulations may offer insight and information that other simple modeling methods cannot provide regarding the problem of BCR-ABL Imatinib Resistance, especially in the case of conformational changes because of remote mutations. Imatinib Resistance mechanisms that were not anticipated previously were revealed by analyzing the interactions between Imatinib and individual residues based on simulation results. This results demonstrated that MD is a powerful way to verify and predict the clinical response or Resistance to Imatinib and to other potential drugs. Cancer 2008. © 2008 American Cancer Society.
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nilotinib is highly active and safe in chronic phase chronic myelogenous leukemia cml cp patients with Imatinib Resistance or intolerance
Blood, 2007Co-Authors: Hagop M Kantarjian, Norbert Gattermann, Jorge E. Cortes, Francis J Giles, Giovanni Martinelli, Andreas Hochhaus, G J Ossenkoppele, Kapil N Bhalla, Ariful Haque, Neil GallagherAbstract:Background: Nilotinib is a novel, selective BCR-ABL inhibitor, designed to bind the ATP-binding site of BCR-ABL protein with higher affinity than Imatinib. It is more potent than Imatinib (IC 50 Methods: This open-label study was designed to evaluate the safety and efficacy of nilotinib in patients (pts) with Philadelphia (Ph + ) Imatinib-resistant or -intolerant CML-CP. Planned nilotinib dose was 400 mg twice daily (BID) with escalation to 600 mg BID for inadequate responses. The primary endpoint was the rate of major cytogenetic response (MCyR) determined on the conventional intent-to-treat patient population. Cytogenetic response (CyR) was assessed by bone marrow karyotyping; peripheral blood FISH was used if a marrow sample cannot be obtained. Results: This analysis includes data from 320 pts who received at least 6 months of nilotinib therapy (70.6% Imatinib-resistant; 29.4% Imatinib-intolerant). The median age was 58 years, the median duration of CML was 57.3 months, and 50.3% were males. Treatment with nilotinib is ongoing in 188 pts (58.8%) and 132 pts (41.3%) discontinued the treatment [51 (15.9%) for disease progression, 51 (15.9%) for adverse events (AE)]. The median duration of nilotinib exposure was 341 (1–624) days and the median average dose intensity was 792.1 mg/d (47.9–1111.6 mg/d). The dose was escalated to 600 mg BID in only 51 pts (15.9%). Complete hematological remission (CHR) at baseline was reported in 114 pts. Of the remaining 206 pts, 157 (76.2%) achieved CHR in 1 month. MCyR was observed in 180 pts (56.3%): 128/320 pts (40.0%) had complete cytogenetic response (CCyR). The median time to CHR and to first MCyR was 1.0 and 2.8 months, respectively. The median duration of MCyR has not been reached. Minor and Minimal CyR was seen in 22 (6.9%) and 42 (13.1%) patients respectively. The most frequent Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (27%), neutropenia (30%), anemia (9%), and asymptomatic serum lipase elevation (15%). Conclusion: The present study confirms nilotinib is an effective therapeutic option in CML-CP pts with Imatinib-Resistance or -intolerance, with an acceptable safety and tolerability profile. With longer follow up, cytogenetic response continues to increase and no change in safety profile has been observed on nilotinib therapy.
Avik Acharya Chowdhury - One of the best experts on this subject based on the ideXlab platform.
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hydroxychavicol a piper betle leaf component induces apoptosis of cml cells through mitochondrial reactive oxygen species dependent jnk and endothelial nitric oxide synthase activation and overrides Imatinib Resistance
Cancer Science, 2012Co-Authors: Jayashree Bagchi Chakraborty, Sanjit K Mahato, Kalpana Joshi, Vaibhav Shinde, Srabanti Rakshit, Nabendu Biswas, Indrani Mukherjee, Labanya Mandal, Dipyaman Ganguly, Avik Acharya ChowdhuryAbstract:Alcoholic extract of Piper betle (Piper betle L.) leaves was recently found to induce apoptosis of CML cells expressing wild type and mutated Bcr-Abl with Imatinib Resistance phenotype. Hydroxy-chavicol (HCH), a constituent of the alcoholic extract of Piper betle leaves, was evaluated for anti-CML activity. Here, we report that HCH and its analogues induce killing of primary cells in CML patients and leukemic cell lines expressing wild type and mutated Bcr-Abl, including the T315I mutation, with minimal toxicity to normal human peripheral blood mononuclear cells. HCH causes early but transient increase of mitochondria-derived reactive oxygen species. Reactive oxygen species-dependent persistent activation of JNK leads to an increase in endothelial nitric oxide synthase-mediated nitric oxide generation. This causes loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, cleavage of caspase 9, 3 and poly-adenosine diphosphate-ribose polymerase leading to apoptosis. One HCH analogue was also effective in vivo in SCID mice against grafts expressing the T315I mutation, although to a lesser extent than grafts expressing wild type Bcr-Abl, without showing significant bodyweight loss. Our data describe the role of JNK-dependent endothelial nitric oxide synthase-mediated nitric oxide for anti-CML activity of HCH and this molecule merits further testing in pre-clinical and clinical settings.
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hydroxychavicol a piper betle leaf component induces apoptosis of cml cells through mitochondrial reactive oxygen species dependent jnk and endothelial nitric oxide synthase activation and overrides Imatinib Resistance
Cancer Science, 2012Co-Authors: Jayashree Bagchi Chakraborty, Sanjit K Mahato, Kalpana Joshi, Srabanti Rakshit, Nabendu Biswas, Labanya Mandal, Dipyaman Ganguly, Avik Acharya Chowdhury, Choudhury Mukherjee, Jaydeep ChaudhuriAbstract:Alcoholic extract of Piperbetle (Piper betle L.) leaves was recently found to induce apoptosis of CML cells expressing wild type and mutated Bcr-Abl with Imatinib Resistance phenotype. Hydroxychavicol (HCH), a constituent of the alcoholic extract of Piper betle leaves, was evaluated for anti-CML activity. Here, we report that HCH and its analogues induce killing of primary cells in CML patients and leukemic cell lines expressing wild type and mutated Bcr-Abl, including the T315I mutation, with minimal toxicity to normal human peripheral blood mononuclear cells. HCH causes early but transient increase of mitochondria-derived reactive oxygen species. Reactive oxygen species-dependent persistent activation of JNK leads to an increase in endothelial nitric oxide synthase-mediated nitric oxide generation. This causes loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, cleavage of caspase 9, 3 and poly-adenosine diphosphate-ribose polymerase leading to apoptosis. One HCH analogue was also effective in vivo in SCID mice against grafts expressing the T315I mutation, although to a lesser extent than grafts expressing wild type Bcr-Abl, without showing significant bodyweight loss. Our data describe the role of JNK-dependent endothelial nitric oxide synthase-mediated nitric oxide for anti-CML activity of HCH and this molecule merits further testing in pre-clinical and clinical settings. (Cancer Sci 2012; 103: 88–99)
Charles L. Sawyers - One of the best experts on this subject based on the ideXlab platform.
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dynamics of chronic myeloid leukaemia
Nature, 2005Co-Authors: Franziska Michor, Susan Branford, Timothy P Hughes, Neil P Shah, Charles L. Sawyers, Yoh Iwasa, Martin A. NowakAbstract:Chronic myeloid leukaemia is associated with the oncogene BCR-ABL. The tyrosine kinase inhibitor Imatinib (Gleevec), in the news as the first molecularly targeted anticancer drug, acts by impairing the function of this oncogene. A study of 169 patients receiving Imatinib followed the kinetics of BCR-ABL in order to develop a mathematical model of the in vivo kinetics of a cancer. Imatinib reduced the rate of leukaemic cell production, but did not appear to deplete a population of leukaemic stem cells. The model also indicates when multiple drug therapy might be more effective than Imatinib alone. The clinical success of the ABL tyrosine kinase inhibitor Imatinib in chronic myeloid leukaemia (CML) serves as a model for molecularly targeted therapy of cancer1,2,3,4, but at least two critical questions remain. Can Imatinib eradicate leukaemic stem cells? What are the dynamics of relapse due to Imatinib Resistance, which is caused by mutations in the ABL kinase domain? The precise understanding of how Imatinib exerts its therapeutic effect in CML and the ability to measure disease burden by quantitative polymerase chain reaction provide an opportunity to develop a mathematical approach. We find that a four-compartment model, based on the known biology of haematopoietic differentiation5, can explain the kinetics of the molecular response to Imatinib in a 169-patient data set. Successful therapy leads to a biphasic exponential decline of leukaemic cells. The first slope of 0.05 per day represents the turnover rate of differentiated leukaemic cells, while the second slope of 0.008 per day represents the turnover rate of leukaemic progenitors. The model suggests that Imatinib is a potent inhibitor of the production of differentiated leukaemic cells, but does not deplete leukaemic stem cells. We calculate the probability of developing Imatinib Resistance mutations and estimate the time until detection of Resistance. Our model provides the first quantitative insights into the in vivo kinetics of a human cancer.
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comparative analysis of two clinically active bcr abl kinase inhibitors reveals the role of conformation specific binding in Resistance
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Michael R Burgess, Neil P Shah, Francis Y Lee, Brian J Skaggs, Charles L. SawyersAbstract:Structural studies suggest that most point mutations in the BCR-ABL kinase domain cause Resistance to the ABL kinase inhibitor Imatinib by impairing the flexibility of the kinase domain, restricting its ability to adopt the inactive conformation required for optimal Imatinib binding, rather than by directly interfering with drug contact residues. BMS-354825, currently in clinical development for Imatinib-resistant chronic myelogenous leukemia, is a dual SRC/ABL kinase inhibitor that binds ABL in both the active and inactive conformation. To examine the potential role of conformational binding properties in drug Resistance, we mapped the mutations in BCR-ABL capable of conferring Resistance to BMS-354825. Through saturation mutagenesis, we identified 10 such BCR-ABL mutations, 8 of which occurred at drug contact residues. Some mutants were unique to BMS-354825, whereas others also conferred Imatinib Resistance. Remarkably, the identity of the amino acid substitution at either of two contact residues differentially affects sensitivity to Imatinib or BMS-354825. The combination of Imatinib plus BMS-354825 greatly reduced the recovery of drug-resistant clones. Our findings provide further rationale for considering kinase conformation in the design of kinase inhibitors against cancer targets.
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overriding Imatinib Resistance with a novel abl kinase inhibitor
Science, 2004Co-Authors: Neil P Shah, Chris Tran, Francis Y Lee, Ping Chen, Derek J Norris, Charles L. SawyersAbstract:Resistance to the ABL kinase inhibitor Imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most Imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to Imatinib that retains activity against 14 of 15 Imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with Imatinib-sensitive and Imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor Resistance can guide the design of second-generation targeted therapies.
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multiple bcr abl kinase domain mutations confer polyclonal Resistance to the tyrosine kinase inhibitor Imatinib sti571 in chronic phase and blast crisis chronic myeloid leukemia
Cancer Cell, 2002Co-Authors: Neil P Shah, B Nagar, Mercedes E Gorre, John Kuriyan, Ronald Paquette, John Nicoll, Charles L. SawyersAbstract:Abstract Through sequencing analysis of blood or bone marrow samples from patients with chronic myeloid leukemia, we identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor Imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups—those that alter amino acids that directly contact Imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for Imatinib binding. Distinct mutations conferred varying degrees of Imatinib Resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression. Multiple independent mutant clones were detected in a subset of relapsed cases. Our data support a clonal selection model of preexisting BCR-ABL mutations that confer Imatinib Resistance.
