Posted by rob on August 29, 2009 under Uncategorized | 
New insights into small-molecule inhibitors of Bcr-Abl.
Med Res Rev. 2009 Aug 27;
Authors: Schenone S, Bruno O, Radi M, Botta M
Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship. (c) 2009 Wiley Periodicals, Inc. Med Res Rev.
PMID: 19714578 [PubMed - as supplied by publisher]
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Posted by rob on August 28, 2009 under Uncategorized |
Dasatinib is an oral potent adenosine triphosphate (ATP)–competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or FcRIIA cross-linking, which require immunoreceptor tyrosine-based activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatin…
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Recent advances in the field of immunology in CML are summarized, specifically those in tumor antigen discovery that have been incorporated into the design of new clinical trials. Cancer Control: Journal of the Moffitt Cancer Center (Source: Medscape Allergy Headlines)
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Authors: Mühlenberg T, Zhang Y, Wagner AJ, Grabellus F, Bradner J, Taeger G, Lang H, Taguchi T, Schuler M, Fletcher JA, Bauer S
Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA), and treatment with the tyrosine kinase inhibitor imatinib yields responses in the majority of patients. However, most patients develop secondary resistance, which is associated with a dismal prognosis. Histone deacetylase inhibitors (HDACI) have been shown to enhance imatinib activity in imatinib-resistant chronic myelogenous leukemia. Against this background, we explored whether HDACI might provide an alternative therapeutic strategy to KIT/PDGFRA kinase inhibitors in GIST. Inhibition of cell proliferation by HDAC…
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Clinical roundtable monograph. Treatment selection for myelodysplastic syndrome patients in the community setting.
Clin Adv Hematol Oncol. 2009 Jul;7(7):S1-15
Authors: Silverman LR, Lyons RM, Shammo JM, Scott BL
Myelodysplastic syndromes (MDS) represent a collection of heterogeneous malignant bone marrow stem cell disorders that result in the production of dysplastic and ineffective blood cells. The disease is marked by gradually worsening cytopenias and a variable risk for the eventual transformation to acute myelogenous leukemia (AML). The risk of developing MDS increases with age, and disease onset before 50 years is unusual. Several morphologic subtypes of MDS have been identified. Each of these subtypes has specific prognostic and morphologic and/or cytogenetic features which make it unique. The International Prognostic Scoring System (IPSS) was developed to aid in determining the prognosis of patients with MDS; this system categorizes patients into four risk groups for both overall survival and transformation to AML: low, intermediate-1, intermediate-2, and high. The management of MDS is based on the goal of controlling cytopenia-related symptoms, improving survival, improving quality of life, and decreasing risk of progression to AML. Treatment strategies include supportive care, iron chelation, treatment with hematopoietic growth factors,immunosuppressive therapies including lenalidomide, antithymocyte globulin, chemotherapy (eg, azacitidine, decitabine, low-dose Ara-C, 7+3 chemotherapy), and stem cell transplantation. However, selecting the appropriate therapy for each individual patient is critical to optimize clinical benefit. This monograph discusses treatment selection for the MDS patient,including a discussion of the overall survival and maintenance of MDS patients, how an appropriate therapy should be chosen in the community setting, and how MDS classification and risk stratification impacts treatment decisions.
PMID: 19708287 [PubMed - in process]
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Differential methylation pattern of ID4, SFRP1, and SHP1 between acute myeloid leukemia and chronic myeloid leukemia.
J Korean Med Sci. 2009 Jun;24(3):493-7
Authors: Uhm KO, Lee ES, Lee YM, Park JS, Kim SJ, Kim BS, Kim HS, Park SH
To gain insight into the differential mechanism of gene promoter hypermethylation in acute and chronic leukemia, we identified the methylation status on one part of 5′CpG rich region of 8 genes, DAB2IP, DLC-1, H-cadherin, ID4, Integrin alpha4, RUNX3, SFRP1, and SHP1 in bone marrows from acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patients. Also, we compared the methylation status of genes in AML and CML using methylation-specific PCR (MSP). The frequencies of DNA methylation of ID4, SFRP1, and SHP1 were higher in AML patients compared to those in CML patients. In contrast, no statistical difference between AML and CML was detected for other genes such as DLC-1, DAB2IP, H-cadherin, Integrin alpha4, and RUNX3. Taken together, these results suggest that these methylation-controlled genes may have different roles in AML and CML, and thus, may act as a biological marker of AML.
PMID: 19543515 [PubMed - indexed for MEDLINE]
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Familial occurrence of chronic myeloid leukemia.
Leuk Lymphoma. 2009 May;50(5):854-6
Authors: Caocci G, Atzeni S, Vacca A, Orrù N, Ledda A, La Nasa G
PMID: 19452324 [PubMed - indexed for MEDLINE]
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Dasatinib overcomes imatinib and nilotinib failure in Philadelphia chromosome positive chronic myeloid leukemia with different mechanisms of resistance.
Leuk Lymphoma. 2009 May;50(5):848-50
Authors: Cannella L, Breccia M, Stefanizzi C, Napoleone L, Santopietro M, Alimena G
PMID: 19367499 [PubMed - indexed for MEDLINE]
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Posted by rob on August 27, 2009 under Uncategorized |
Conclusion: This is the first report of development of LSetA, a sclerosing dermatosis, while receiving a therapeutic dose of imatinib mesylate, a drug thought to have anti-sclerotic properties. Skupsky H, Abuav R, High W, Pass C, Goldenberg G. Development of lichen sclerosus et atrophicus while receiving a therapeutic dose of imatinib mesylate for chronic myelogenous leukemia. (Source: Journal of Cutaneous Pathology)
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Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia.
Biologics. 2008 Sep;2(3):491-500
Authors: Karp JE, Lancet JE
Farnesyltransferase inhibitors (FTIs) represent a new class of signal transduction inhibitors that block the processing of cellular polypeptides that have cysteine terminal residues and, by so doing, interdict multiple pathways involved in proliferation and survival of diverse malignant cell types. Tipifarnib is an orally bioavailable, nonpeptidomimetic methylquinolone FTI that has exhibited clinical activity in patients with myeloid malignancies including elderly adults with acute myelogenous leukemia (AML) who are not candidates for traditional cytotoxic chemotherapy, patients with high-risk myelodysplasia, myeloproliferative disorders, and imatinib-resistant chronic myelogenous leukemia. Because of its relatively low toxicity profile, tipifarnib provides an important alternative to traditional cytotoxic approaches for elderly patients who are not likely to tolerate or even benefit from aggressive chemotherapy. In this review, we will focus on the clinical development of tipifarnib for treatment of newly diagnosed AML, both as induction therapy for elderly adults with poor-risk AML and as maintenance therapy following achievement of first complete remission following induction and consolidation therapies for poor-risk AML. As with all other malignancies, the optimal approach is likely to lie in rational combinations of tipifarnib with cytotoxic, biologic and/or immunomodulatory agents with non-cross-resistant mechanisms of action. Gene expression profiling has identified networks of differentially expressed genes and gene combinations capable of predicting response to single agent tipifarnib. The clinical and correlative laboratory trials in progress and under development will provide the critical foundations for defining the optimal roles of tipifarnib and in patients with AMl and other hematologic malignancies.
PMID: 19707379 [PubMed - in process]
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Inhibitors of Deacetylases Suppress Oncogenic KIT Signaling, Acetylate HSP90, and Induce Apoptosis in Gastrointestinal Stromal Tumors.
Cancer Res. 2009 Aug 25;
Authors: Mühlenberg T, Zhang Y, Wagner AJ, Grabellus F, Bradner J, Taeger G, Lang H, Taguchi T, Schuler M, Fletcher JA, Bauer S
Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA), and treatment with the tyrosine kinase inhibitor imatinib yields responses in the majority of patients. However, most patients develop secondary resistance, which is associated with a dismal prognosis. Histone deacetylase inhibitors (HDACI) have been shown to enhance imatinib activity in imatinib-resistant chronic myelogenous leukemia. Against this background, we explored whether HDACI might provide an alternative therapeutic strategy to KIT/PDGFRA kinase inhibitors in GIST. Inhibition of cell proliferation by HDACI was seen in KIT-positive but not in KIT-negative GIST cell lines, suggesting that HDACI activity is mainly conferred by targeting oncogenic KIT. KIT activity, expression, and activation of downstream pathways were strongly inhibited by several HDACI (SAHA, LBH589, VPA, trichostatin A, and NaButyrate). SAHA and LBH589 induced apoptosis in KIT-positive GIST, and strong synergism with imatinib was observed at low concentrations of SAHA and LBH589. Mechanistically, treatment with HDACI reduced KIT mRNA transcript levels and led to strong acetylation of HSP90, interfering with its activity as KIT chaperone. These results provide preclinical evidence for a disease-specific effect of HDACI in KIT-positive GIST, which could translate into therapeutic activity. [Cancer Res 2009;69(17):6941-50].
PMID: 19706776 [PubMed - as supplied by publisher]
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Development of lichen sclerosus et atrophicus while receiving a therapeutic dose of imatinib mesylate for chronic myelogenous leukemia.
J Cutan Pathol. 2009 Aug 23;
Authors: Skupsky H, Abuav R, High W, Pass C, Goldenberg G
Background: Imatinib mesylate (Gleevec((R))) is a selective Bcr-Abl protein tyrosine-kinase inhibitor, and it also inhibits the receptor tyrosine kinases for stem cell factor (c-kit) and platelet-derived growth factor (PDGFR). It is being investigated for use in the treatment of sclerosing dermatoses. Observation: A 44-year-old woman with a history of chronic myelogenous leukemia (CML) was referred for the evaluation of a pruritic eruption that developed over 6 months. Examination revealed atrophic plaques confined to the groin, vulva, axillae, inframammary region, trunk, antecubital and popliteal fossae, and posterior thighs bilaterally. A biopsy showed lichen sclerosus et atrophicus (LSetA). At the time of presentation, the patient was receiving imatinib mesylate 400 mg daily for CML. Conclusion: This is the first report of development of LSetA, a sclerosing dermatosis, while receiving a therapeutic dose of imatinib mesylate, a drug thought to have anti-sclerotic properties. Skupsky H, Abuav R, High W, Pass C, Goldenberg G. Development of lichen sclerosus et atrophicus while receiving a therapeutic dose of imatinib mesylate for chronic myelogenous leukemia.
PMID: 19703239 [PubMed - as supplied by publisher]
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New directions in the treatment of imatinib failure and/or resistance.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S27-33
Authors: Giles FJ
For the minority of chronic myeloid leukemia (CML) patients who demonstrate primary or secondary resistance or intolerance to first-line imatinib therapy, previously available treatment options were limited to cytotoxic chemotherapy, interferon alfa, or allogeneic hematopoietic stem cell transplantation. While the latter option remains a possibility for some, strong clinical efficacy data from recent phase II trials have led to the approval of two second-generation tyrosine kinase inhibitors (TKIs), nilotinib and dasatinib, for the treatment of CML following imatinib failure and/or resistance. Treatment guidelines now recommend either of these two agents as second-line therapy for most patients, although the decision of which second-generation agent to use remains subjective, and is often dependent on the agents’ tolerability profiles, as comparative efficacy data from head-to-head clinical studies are not available. Sequential treatment with all three TKIs over the course of the disease is also a possibility, as both nilotinib and dasatinib have shown activity in patients with resistance to imatinib and a subsequent TKI. Novel therapeutic options are continually being developed to expand the range of treatment options, and new tyrosine kinase inhibitors or agents with other mechanisms of action, such as histone deacetylase inhibitors, may prove effective in patients with resistance or intolerance to multiple agents.
PMID: 19621547 [PubMed - indexed for MEDLINE]
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Understanding the role of mutations in therapeutic decision making for chronic myeloid leukemia.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S22-6
Authors: Jabbour E, Soverini S
In patients with chronic myeloid leukemia (CML) resistant to imatinib, resistance is commonly associated with mutations in the BCR-ABL protein. Approximately 85% to 90% of resistance-associated mutations occur within the ABL kinase domain, and confer resistance either directly, by blocking imatinib binding, or indirectly, by altering the conformation of BCR-ABL. The degree of resistance depends on the mutation, with some remaining sensitive to imatinib. Imatinib dose escalation may overcome resistance in some of these patients or therapy can be switched to the second-generation tyrosine kinase inhibitors (TKIs) nilotinib or dasatinib. The long-term efficacy of second-generation TKIs may also be related to specific BCR-ABL mutations, with the T315I mutant remaining resistant to all currently available TKIs. Other treatments, including investigational agents, may be options for patients with this mutation. The choice of therapy should be guided by multiple factors, including mutational analysis, disease phase, patient characteristics, and the safety profile of the agents.
PMID: 19621546 [PubMed - indexed for MEDLINE]
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Practical considerations for the management of patients in the tyrosine kinase inhibitor era.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S16-21
Authors: O’Dwyer M, Atallah E
Most tyrosine kinase inhibitor (TKI)-associated adverse events are easily managed by symptomatic relief, although dose reductions or interruptions may be necessary in some patients. Long-term follow-up of early clinical trials has shown that the majority of imatinib-associated adverse events generally occur early, and the incidence decreases over the course of therapy, making imatinib the treatment of choice for long-term administration. A lack of patient adherence to imatinib, due to the occurrence of adverse events or for other reasons, can decrease response rates, and may cause resistance or disease relapse. Patient adherence to TKI therapies is a critical consideration for successful, long-term management of patients with chronic myeloid leukemia (CML). In patients who remain intolerant to imatinib, the differing tolerability profiles of second-generation TKIs should be considered when determining a therapeutic course of action. Throughout the course of therapy for CML, early and successful management of adverse events will increase dose optimization and patient adherence, and thereby optimize responses.
PMID: 19621545 [PubMed - indexed for MEDLINE]
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Clinical strategies to achieve an early and successful response to tyrosine kinase inhibitor therapy.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S11-5
Authors: Hughes T, Hochhaus A
Imatinib is the standard of care for previously untreated chronic myeloid leukemia (CML), with high response rates that lead to improved event-free and overall survival compared with interferon alfa. Imatinib dose is one important factor affecting response, and early clinical studies showed promising molecular response rates with high-dose therapy. Large, randomized trials are now ongoing to test this potential benefit and establish whether a starting dose of 800 mg/d improves long-term clinical outcomes compared with the current standard dose of 400 mg/d. Low plasma imatinib levels are associated with a decreased chance of response. The importance of imatinib dosing and plasma levels is likely due to their impact on intracellular concentrations of the drug. Cellular influx of imatinib is mediated by the OCT-1 protein, and patients with low OCT-1 activity may benefit from dose-intensive therapy. For nonresponding or slowly responding patients, dose escalation to 600 to 800 mg/d may lead to durable responses in patients with primary or secondary resistance. Regular monitoring of response is crucial to maximize therapeutic success, and improved understanding of the factors affecting response will guide future clinical strategies.
PMID: 19621544 [PubMed - indexed for MEDLINE]
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Optimizing first-line therapy for patients with chronic myeloid leukemia.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S5-10
Authors: Fava C, Cortes J
Imatinib is now established as the gold standard first-line therapy for patients with chronic myeloid leukemia (CML). Responses to imatinib are superior to those seen with interferon alfa and also occur earlier, demonstrating a stronger and deeper response to therapy. Imatinib therapy also provides long-term clinical benefit and outcomes, with improved progression-free survival (PFS) and overall survival (OS) compared with historical controls, at 6 years of follow-up. Recent data show that annual event rates decline over time with imatinib therapy, suggesting that long-term disease control is possible in continuously responding patients. Despite these treatment successes, new strategies are continually being evaluated to maximize responses to imatinib and ensure the best treatment outcomes for all patients. For example, high-dose imatinib therapy, with doses up to 800 mg/d, has been shown to improve response rates. Prospective, randomized trials are ongoing to assess the benefits of high-dose imatinib therapy and determine whether it extends PFS and OS compared with standard-dose imatinib.
PMID: 19621543 [PubMed - indexed for MEDLINE]
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New directions in the treatment of patients with chronic myeloid leukemia: introduction.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S1-4
Authors: Baccarani M
PMID: 19621542 [PubMed - indexed for MEDLINE]
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Response dynamics in chronic-phase chronic myeloid leukemia.
Clin Lymphoma Myeloma. 2009 Jun;9(3):217-22
Authors: Mauro MJ
Cytogenetic response (CyR), especially complete CyR (CCyR), has historically and is currently associated with a significant survival advantage in patients with chronic-phase chronic myeloid leukemia (CP-CML). CCyR represents a critical level of disease reduction irrespective of treatment type, and timely achievement demonstrates treatment-sensitive disease. Guidelines from European LeukemiaNet and the National Comprehensive Cancer Network therefore state that alternative therapies should be considered for patients not achieving CCyR by 6 or 12 months. Data from clinical trials indicate that early CCyR affords the best benefit:risk ratio by minimizing the mounting risk of disease progression, and the duration of CCyR when achieved affects disease progression. Treatment options for patients who fail to achieve CCyR on standard-dose imatinib (400 mg/day) include imatinib dose escalation, dasatinib, nilotinib, stem-cell transplantation, or a clinical trial. While molecular testing gauges further risk reduction, disease stability, and often elimination of BCR-ABL transcripts below detection threshold, CCyR remains the most important surrogate for long-term survival and cytogenetic testing remains a key part of patient care in the management of CML, particularly early in response. Longerterm follow-up data will be required to confirm CCyR as a surrogate marker for survival in imatinib-resistant patients treated with the secondgeneration tyrosine kinase inhibitors, dasatinib and nilotinib.
PMID: 19525190 [PubMed - indexed for MEDLINE]
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Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia.
Eur Respir J. 2009 Mar;33(3):670-2
Authors: Daniels JM, Vonk-Noordegraaf A, Janssen JJ, Postmus PE, van Altena R
Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are several reports suggesting that imatinib might impair the immune system, leading to a variety of infections, including varicella zoster and hepatitis B. Control of TB in healthy individuals is achieved through acquired immunity, in which antigen-specific T-cells and macrophages arrest growth of Mycobacterium tuberculosis bacilli and maintain control over persistent bacilli. In the chronic stage of the infection, CD8+ T-cells assist macrophages in controlling intracellular mycobacteria. The T-cell receptor orchestrates this process. The fact that tyrosine kinases play an important role in T-cell receptor signal transduction and that imatinib has been shown to affect T-cell receptor signal transduction, presents a mechanism by which imatinib might impair control of Mycobacterium tuberculosis; thereby leaving the host susceptible to reactivation of tuberculosis.
PMID: 19251803 [PubMed - indexed for MEDLINE]
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