Jean Pierre Issa

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..It is also a pioneering example of an agent that targets 'epigenetic' gene silencing, a mechanism that is exploited by cancer cells to inhibit the expression of genes that counteract the malignant phenotype...

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..To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia...

..The contribution of epigenetic changes to the altered immune function observed in aging humans deserves careful investigation...

..There was no correlation between P15 methylation at baseline or after therapy and response to decitabine. We conclude that decitabine is effective in myeloid malignancies, and low doses are as or more effective than higher doses...

..There are at least three different subsets with distinct clinico-pathologic features, with important implications for preventions, screening, and therapy...

..These advances have turned this agent from just another cytosine analogue into a targeted drug aimed at reversing epigenetic silencing in cancer cells. Here, recent clinical and translational studies with decitabine are reviewed...

..Furthermore, CIMP-associated cancers seem to have a distinct epidemiology, a distinct histology, distinct precursor lesions and distinct molecular features...

..In the future, combination strategies to increase gene reactivation and to take advantage of increased expression of target genes may be critical for achieving optimal results...

..These drugs have now been approved for clinical use in the United States in the treatment of myelodysplastic syndrome, thus opening the floodgate for a whole new approach to cancer therapy--epigenetic therapy...

..Here, we discuss the implications of this work in terms of the etiology, risk, and potential prevention of cancer...

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..It is suggested that epigenetic variation related to aging, lifestyle, exposures and possibly genetic factors, is one of the modulators of acquired, age-related human diseases, including neoplasia...

..Reactivation of both the silenced paternal and imprinted maternal alleles can be achieved by demethylation and inhibition of histone deacetylation...

..Outcome of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) with chromosome 5 and 7 abnormalities (excluding del 5[q]) has been poor, with <10% of patients alive at 2 years...

..Decitabine is a hypomethylating agent that has shown encouraging preliminary anti-CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML...

..Complete remission was achieved in 2 of 6 minimally pre-treated patients. We conclude that the combination of azacitidine and cytarabine is feasible but has limited activity in relapsed/refractory AML...

..The comparative efficacy of these 2 forms of treatment in MDS is unknown. The objective of the current study was to compare the efficacy and toxicity profiles of decitabine and intensive chemotherapy in MDS...

..Our results suggest that reduced H3 Lys-4 methylation and increased H3 Lys-9 methylation play a critical role in the maintenance of promoter DNA methylation-associated gene silencing in colorectal cancer...

..Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known...

..This study was conducted to determine whether RAR-beta(2) gene expression in such lesions can be silenced by promoter methylation...

..To define the prognosis in myelodysplastic syndrome (MDS) and deletion 5q with or without other cytogenetic abnormalities...

..In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks...

..The prognosis of patients with myelodysplastic syndrome (MDS) after decitabine failure is not known...

..003). These results indicate that differences in DNA methylation of specific molecular pathways may contribute to the prognostic differences known to occur between pediatric and adult patients with ALL...

..The simulations show that the proposed design saves sample size, has better power, and efficiently assigns more patients to doses with higher efficacy levels...

..In this article, we provide a brief introduction to the field of histone deacetylation inhibition in cancer and review the most relevant clinical data so far published...

..In this study, the authors update their experience with decitabine in patients with MDS and analyze the cytogenetic response patterns and prognostic factors associated with decitabine therapy...

..To our knowledge, the feasibility of therapy with hypomethylating agents (HAs) in patients with renal insufficiency (RI) has not been examined...

..There are still some issues concerning the ideal dose and schedule of decitabine for treating patients with MDS. This article focuses on the most recent clinical studies of decitabine for therapy of MDS...

..These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation...

..This review focuses on supportive care modalities, the approved agents indicated for the treatment of MDS and future directions for the treatment of MDS, including agents under clinical investigation...

..In patients with MDS, it was recently demonstrated that epigenetic therapy with hypomethylating agents improved survival. Much therapeutic progress has been witnessed in leukemia and MDS, and much more is expected to occur soon...

..We also show that homozygous inactivation of P2RY5 was antecedent to the loss of RB1 during tumor development, and that nucleotide substitutions in P2RY5 represent a cancer predisposing factor...

..We conclude that promoter DNA methylation can be differentially regulated and DeltaDNMT3Bs are involved in regulation of such promoter-specific de novo DNA methylation...

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..In summary, these results provide rationale for the combined targeting of RAR and PPARgamma nuclear receptors in the therapy of APL...

..Drugs that inhibit DNA methylation and histone deacetylation are in use in the clinic and should be tested in colorectal malignancy...

..Two imprinted genes, paternally expressed 3 (PEG3) and aplasia Ras homologue member I (ARHI), are the most frequently down-regulated in ovarian cancers on gene expression arrays...

..The DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) is frequently methylated in colorectal cancer. We hypothesized that MGMT methylation could be one of the mediators of field cancerization in the colon mucosa...

..Our data identify new targets of transcriptional silencing in cancer, and provide new biomarkers that could be useful in screening for prostate cancer and other cancers...

..Other epigenetic modifications such as hypermethylation in CpG island III may also contribute to the loss of ARHI expression...

..Investigations of combinations of decitabine with other agents, including histone deacetylase inhibitors, are currently ongoing in the hope of substantially prolonging survival in patients with hematologic malignancies...

..We conclude that clinically significant responses with decitabine can be seen in patients post-azacitidine failure without significant toxicity...

..Combination therapies that augment the epigenetic effect of decitabine will likely improve responses and extend its use for the treatment of other malignancies...

..By hypomethylating genes, decitabine may up-regulate factors required for chemotherapeutic cytotoxicity. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1...

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..Together, our integrated genetic and epigenetic analysis reveals that colon cancers correspond to three molecularly distinct subclasses of disease...

..These results demonstrate that oncogenic PML-RARalpha and AML1-ETO translocations are rarely associated with RARbeta2 promoter methylation in primary AML samples...

..In MDS, RIL methylation is a marker of adverse prognosis independent of chromosome 5 and 7 deletions. Our data suggest that RIL is a good candidate TSG silenced by hypermethylation in cancer...

..Understanding epigenetic alterations as a driving force in neoplasia opens new fields of research in epidemiology, risk assessment, and treatment in CRCs...

..Ongoing studies will determine whether changes in LINE-1 methylation in plasma DNA occur as a result of treatment with DNA methylation inhibitors and parallel changes in tumor tissue DNA...

..VPA blood levels were higher in responders (P < .005). In conclusion, the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as no. NCT00326170...

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..The variability within and between cell lines and tumor specimens supports a heterogeneous and dynamic state of methylation in genes associated with HNSC tumorigenesis...

..This unbiased approach confirms the tight coupling between DNA methylation and histone modifications in cancer and could be used to probe gene silencing in nonneoplastic conditions as well...

..Several techniques useful in epigenetic data analysis will be discussed, mapping tags to reference genome incorporating all known SNPs, analysis of chIP-seq data, as well as restriction enzyme-based DNA methylation analysis...

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..The present study was undertaken to determine whether methylation of a set of growth-suppressor genes would correlate to the expression of estrogen receptors (ERs) and progesterone receptors (PRs)...

..We examined the extent of gene methylation in pathologically normal human prostate as a function of age...

..We sought to determine the prognostic significance of CIMP in advanced colorectal cancer patients treated with 5-fluorouracil (5-FU) in an Eastern Cooperative Oncology Group clinical trial...

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..Our data suggest a predominantly noncytotoxic mechanism of action for decitabine, leading to altered biology of the neoplastic clone and/or normal cells. This trial was registered at www.ClinicalTrials.gov as #NCT00067808...

..No agent in this class has been studied in a phase III trial, but several agents have been or are being studied in phase II trials. Further research is needed to determine the appropriate patient selection and dosing schedules...

..Herein, we summarize the results of recent clinical trials of decitabine in hematologic malignancies, and review the translational research into decitabine's mechanism of clinical activity...

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..A Phase II study was performed on low-dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP)...

..This method can be used as a surrogate marker of genome-wide methylation changes. In addition, it is less labor intensive and requires less DNA than previous methods of assessing global DNA methylation...

..The new design uses fewer patients, and can more effectively assign patients to the better treatment arms. We demonstrate these properties through simulation studies...

..DNMT-1 has a direct suppressive role in 15-LOX-1 transcriptional silencing that is independent of 15-LOX-1 promoter DNA methylation...

..Recent studies showed that EGFR inhibitors are effective for patients with HNSCC. This study analyzed the genetic nature of EGFR gene in HNSCC and its clinical correlations...

..03). Loss of p16 protein expression correlated with methylation of p16 gene in carcinoid tumors (p = 0.006). Our study indicates that methylation profile of carcinoid tumors differs from PETs, reflecting different molecular pathogenesis...

..In summary, MCAM is a suitable technique to discover methylated genes and to profile methylation changes in clinical samples in a high-throughput fashion...

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..Our results confirm that epigenetic profiles are useful in identifying molecular mediators for cancer drug sensitivity (pharmaco-epigenomics)...

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..Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters...

..Aberrant methylation of promoter-associated CpG islands is an epigenetic oncogenic mechanism. The objective of this study was to define the methylation characteristics of patients with acute lymphocytic leukemia (ALL)...

..This epigenetic modification has been associated with gene silencing, malignant transformation, and aging. It is not known whether there are epigenetic differences between pediatric patients and adult patients with ALL...

..Even with all the information we have learned, there is still a need to determine the optimal dosing schedule and the development of alternative dosing forms...

..Patients with methylation at all four loci were 14 times more likely to have a family history of cancer than patients with methylation at none of the four loci. These findings suggest that there may be a genetic component to CIMP in CRC...

..These findings reveal that the expression of RARbeta1 is regulated by cell density through changes in histone acetylation...

..These findings indicate that silencing of TIG1 promoter by hypermethylation is common in human cancers and may contribute to the loss of retinoic acid responsiveness in some neoplastic cells...

..We identified pretreatment and treatment-associated factors that were associated with higher major cytogenetic response rates and with improved survival...

..We conclude that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS...

..Imatinib mesylate, a specific Bcr-Abl tyrosine kinase inhibitor, has shown encouraging activity in chronic myelogenous leukemia (CML)...

..To study the role of DNA methylation in relapse mechanisms in acute lymphocytic leukemia (ALL), we have compared the methylation status of five genes at the time of initial presentation and at first relapse in 25 adult patients with ALL...

..We conclude that the JAK2 1849G>T mutation is common in Ph(-) MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias...

..6%; P<.001). CONCLUSION: Geographic variations in the methylation status of various CpG islands indicate that environmental factors may influence the frequent and concordant degree of hypermethylation in multiple genes in HCC tumors...

..The hypermethylator phenotype is related to patient-specific factors, such as carcinogenic exposure or genetic predisposition...

..5-Aza-2'-deoxycytidine (DAC) is a cytosine analogue that inhibits DNA methylation and also has activity in myeloid leukemia. Therefore, we investigated combining these two drugs in human leukemia cell lines in vitro...

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..Our finding demonstrates that, in some genes, hypermethylation in cancer is dictated by protein-DNA interactions at the promoters and provides a novel mechanism by which genetic polymorphisms can influence an epigenetic state...

..02). Our results indicate that p57KIP2 is frequently methylated in adult patients with ALL, and that inactivation of a pathway composed of p73, p15, and p57KIP2 predicts for poor prognosis in Ph-negative patients...

..Through this leukemia SPORE, our research team will make a significant impact on leukemia prognosis. ..

..This grant will support the first testing, in a randomized setting, of combined epigenetic therapy, with both molecular and clinical endpoints. ..

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..These studies should provide definitive information on interactions between diet and DNA methylation in human colorectal mucosa and cancer. ..

..Ultimately, this work aims at establishing that methylation profiling may carry the same clinical implications as that already established for genetic profiling in neoplasia. ..

..Ultimately, methylation profiling may prove very valuable in identifying subsets of patients with distinct clinical courses and response to specific therapeutic interventions, including using methylation inhibitors. ..

..This grant will support the first testing, in a randomized setting, of combined epigenetic therapy, with both molecular and clinical endpoints. ..