Brian Druker

..Finally, the potential use of STI571 with different tumors and the translation of this paradigm to other malignancies are explored...

..Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy...

..Lastly, the potential use of STI571 in other malignancies and the translation of this paradigm to other malignancies is explored...

..Despite the success of imatinib, there remains much skepticism that this paradigm will be applicable to more complicated solid tumors. Whether this skepticism is appropriately deserved will be discussed...

..Future directions including the mechanisms and management of resistance and new therapeutic strategies are discussed. Finally, the literature supporting the use of STI571 in other malignancies, including solid tumors is briefly reviewed...

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..Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML...

..For example, how durable will responses to imatinib mesylate be and is it necessary or possible to improve upon these results? Ongoing efforts to address these issues will be discussed...

..The clinical development of imatinib illustrates the effectiveness of targeting molecular pathogenetic events. Hopefully, this example can be extended to other malignancies...

..The treatment recommendations are intended to optimize therapy with imatinib while taking into account a patient's specific circumstances...

..Continued studies of hematologic malignancies will allow this paradigm of targeting molecular pathogenetic events to be applied to many additional hematologic cancers...

..BCR-ABL-kinase domain mutations in patients with a stable CCR are infrequent, and their detection does not consistently predict relapse. Alternative mechanisms must be responsible for disease persistence in the majority of patients...

..Early detection of emerging mutant clones may aid in guiding decisions regarding alternative treatment options...

..Integration of STI571 into CML treatment algorithms will require long-term follow-up data from the ongoing phase II and III clinical studies...

..The results of clinical studies to date are highly encouraging and STI571 promises to be an important addition to the therapy of CML...

..The results of clinical studies have demonstrated the potential of molecularly targeted therapies, and ST1571 is emerging as a new therapeutic agent for CML...

..The clinical features, molecular pathogenesis, and current treatment options of CML are reviewed along with the development of STI571, the phase I clinical results, and the application of this paradigm to other malignancies...

..This compound may be useful in treating cancers associated with increased c-kit kinase activity...

..Through rational drug development, STI571, a bcr-abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product-targeted therapy, offering new hope for expanded treatment options for patients with CML...

..Thus, it will be important to investigate the prognostic impact of coexpression of deletion mutants in CML patients during imatinib treatment...

..Through rational drug development, STI571, a bcr-abl tyrosine kinase inhibitor, has emerged as targeted therapy that offers new hope for expanded treatment options for patients with CML...

..Clinicians should be aware that possession of the arginine allele of K247R does not reflect a mutation that necessitates a change in the therapeutic strategy, unless there are other signs of inadequate response to drug...

..Second, we analyze preliminary clinical data of ongoing combination studies. Finally, we provide a summary of approaches that use novel antileukemic agents with molecularly characterized modes of action...

..The presence of clonal abnormalities in Ph-negative cells of imatinib-treated CML patients with MCR and CHR highlights the importance of routine metaphase cytogenetic testing and long-term follow-up of all imatinib-treated patients...

..This study details the growth phenotype of seven pediatric patients maintained in remission on imatnib mesylate over an extended period of time...

..A direct interaction between Crkl and Abl has also been shown using a yeast two-hybrid screen...

..Collectively this data argues against a critical role for BTK in Bcr-Abl-mediated leukemogenesis...

..Such patients may be eligible for allogeneic stem cell transplantation (SCT), raising the question whether imatinib therapy may compromise the outcome of subsequent SCT...

..Our data support the concept that SH1 domains determine the final sites of phosphorylation once PTKs reach their target proteins...

..These findings suggest both direct and indirect interactions of CRKL with BCR-ABL. Thus, disruption of the direct interaction with BCR-ABL has not excluded a role for CRKL in BCR-ABL-mediated transformation...

..Shd was tyrosine phosphorylated in COS-7 cells co-transfected with Shd and c-Abl or Bcr-Abl. These results suggest that Shd may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system...

..Thus, a direct interaction of CRKL and BCR-ABL is not required for CRKL to become tyrosine phosphorylated by BCR-ABL and suggests that CRKL function may still be required for BCR-ABL function through an indirect interaction...

..These findings illustrate the biological importance of gain-of-function JAK3 mutations in leukemogenesis and demonstrate the utility of proteomic approaches to identifying clinically relevant mutations...

..The drug resistance and transformation potency of mutants may determine the outcome of patients on therapy with Abl kinase inhibitors...

..Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity...

..However, sequencing uniformly revealed T315I, consistent with the need for a T315I inhibitor, to completely block resistance...

..In conclusion, within the limitation of this historical comparison, there is a survival advantage from first-line therapy with imatinib over IFN/Ara-C...

..This strategy warrants further attention in Bcr/abl(+) hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors...

..Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations...

..Together, these advances are contributing to a high level of disease control, and might ultimately lead to disease eradication...

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..Tandutinib at the MTD (525 mg twice daily) should be evaluated more extensively in patients with AML with FLT3-ITD mutations to better define its antileukemic activity...

..These results demonstrate that Bim and Bad account for most, perhaps all, imatinib-induced killing of Bcr/Abl+ leukemic cells and suggest previously undescribed drug combination strategies for cancer therapy...

..Together, this work supports the inhibition of translation initiation as a therapeutic strategy for treating cancers fueled by dysregulated translation...

..Activation of p38 MAPK mediated the drug's effects on inflammatory cytokine production in macrophages but not LLC1 cytotoxicity and this was confirmed with inhibitor studies...

..Altogether, our studies identify a novel mechanism by which BCR-ABL may promote leukemic cell growth, involving sequential engagement of the mTOR/p70 S6K pathway and downstream suppression of PDCD4 expression...

..Although no value of EGFR expression in prognosis was found, our findings are likely to have implications in the design of clinical trials targeting the EGFR family of proteins in breast cancer...

..Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients...

..The development of imatinib validates an emerging paradigm in cancer, in which a tumor is defined by genetic abnormalities and effective therapies are developed that target events critical to the growth and survival of a specific tumor...

..Through rational drug development, STI571, a Bcr-Abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product targeted therapy, offering new hope for expanded treatment options for patients with CML...

..This trial was registered at www.clinicaltrials.gov as CA180013...

..Inhibition of LPAAT-beta induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-beta as a potential drug target in neoplasia...

..These studies identified a novel function of SHP-2 and suggest that SHP-2 might be a useful target for controlling Bcr-Abl-positive leukemias...

..Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs...

..Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy...

..Following this initial interaction, Cbl can then become tyrosine phosphorylated and interact with the SH2 domain of Bcr-Abl, further stabilizing the complex...

..We conclude that resistance of primary CML cells that are insensitive to imatinib may be the result of molecular properties causing drug resistance rather than a consequence of quiescence itself...

..Further studies are warranted to test the effects of imatinib in combination with other agents and to define the mechanisms of resistance to imatinib...

..These data underline the importance of resistance testing and provide a rational approach for dose-adjusted administration of imatinib when combined with other agents...

..Thus, STI571 has emerged as a paradigm for gene product targeted therapy, offering expanded treatment options for patients with CML...

..Although all patients demonstrated an initial decrease in bone marrow cellularity after imatinib mesylate therapy, continued follow-up showed that histopathologic findings correlated with genetic response...

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..Quality of life (QOL) outcomes in patients with chronic myeloid leukemia (CML) were evaluated in an international phase III study...

..J. Virol. 76(16): 8383-8399). These data demonstrate that microarrays are useful for the identification of pharmacological targets essential for KS tumorigenesis...

..This study highlights the need for biochemical and biologic characterization, before a resistant phenotype can be ascribed to a mutant...

..Once patients have other signs of acceleration, clonal evolution predicts lower response rates and a shorter time to treatment failure...

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..KD mutants present at low levels do not invariably lead to relapse, and additional factors are required to induce a fully drug-resistant phenotype...

..However, a subgroup of patients is refractory at the cytogenetic level. Clinically, it would be advantageous to identify such patients a priori, since they may benefit from more aggressive therapy...

..In conclusion, rapamycin inhibits growth of CML cells in vitro and in vivo and, in addition, down-regulates expression of VEGF. Both effects may contribute to the antileukemic activity of the drug in CML...

..Thus, AP23464 and AP23848 potently and selectively target activation-loop mutants of Kit in vitro and in vivo and could have therapeutic potential against D816V-expressing malignancies...

..The implications of these results, and the potential role this and other novel ABL inhibitors may have in treating patients with CML, are discussed...

..This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I...

..Issues related to clinical trials of molecularly targeted agents are discussed, including patient and dose selection. Last, the translation of this paradigm to other malignancies is explored...

..These studies demonstrate the importance and impact of conducting scientific studies as part of clinical trials...

..As phase 1 clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations...

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..The aim of this study was the preclinical evaluation of imatinib mesylate (Gleevec, formerly STI571) in conjunction with arsenic trioxide (As2O3, Trisenox) for the treatment of chronic myelogenous leukemia (CML)...

..In analogy to imatinib mesylate in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols...

..We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML...

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..By facilitating the development of these drugs, we hope to improve the outcome for patients with cancer as rapidly as possible. ..

..Combined, these data should offer significant insights into the biology of and the mechanism of transformation by Bcr-Abl. ..

..Many are now funded by the National Cancer Institute (NCI). ..

..Combined, these data should offer significant insights into the biology of and the mechanism of transformation by Bcr-Abl. ..

..Through these studies the investigators should gain a greater understanding of the contribution of tyrosine phosphorylation of Cbl to its function and the role of Cbl in myeloid transformation. ..

..Through these studies, it is hoped to be able to design specific therapeutic agents for the treatment of this disease. ..