Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies

Fandy, Tamer E.; Herman, James G.; Kerns, Patrick W.; Jiemjit, Anchalee; Sugar, Elizabeth A.; Choi, Si Ho; Yang, Allen S.; Aucott, Timothy; Dauses, Tianna; Odchimar-Reissig, Rosalie; Licht, Jonathan D.; McConnell, Melanie J.; Nasrallah, Chris A.; Kim, Marianne K.H.; Zhang, Weijia; Sun, Yu; Murgo, Anthony J.; Espinoza‐Delgado, Igor; Oteiza, Katharine; Owoeye, Ibitayo; Silverman, Lewis R.; Gore, Steven D.; Carraway, Hetty E.

doi:10.1182/blood-2009-02-203547

Cited by 266 publications

(235 citation statements)

References 43 publications

(61 reference statements)

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“…13,14 However, changes in CDKN2B, CDH1, DAPK1 and SOCS-1 gene expression upon therapy did not correlate with the response. 15 Our results show that Fas re-expression correlated with the response and that low Fas protein expression at diagnosis, which associated with hypermethylation of the FAS gene promoter, is a predictive biomarker of the response to azacitidine, independently of IPSS and prior therapy, even if the re-activation of Fas may not be the sole determinant of the response. By contrast, Fas level at diagnosis had no impact on the overall survival.…”

Section: Letters To the Editormentioning

confidence: 63%

Fas expression at diagnosis as a biomarker of azacitidine activity in high-risk MDS and secondary AML

et al. 2012

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Section: Letters To the Editormentioning

confidence: 63%

Fas expression at diagnosis as a biomarker of azacitidine activity in high-risk MDS and secondary AML

et al. 2012

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“…Hypomethylating agents are active in both MDS and AML, even if their mechanisms of action are not fully characterized [15,16]. Indeed, Azacitidine (AZA) has demonstrated a survival benefit over conventional care regimens [best supportive care (BSC), low-dose cytarabine, or intensive chemotherapy] in higher risk MDS (including AML with 20 to 30% blasts) and has become the standard of care in MDS patients not eligible for allogeneic stem cell transplantation (allo-SCT) [17,18].…”

Section: Introductionmentioning

confidence: 99%

Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities

et al. 2015

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Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation.

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“…These conditions are generally assumed to maximize DNA demethylation responses, and several studies have confirmed that drug-induced DNA demethylation occurs in patients (Issa et al, 2005;Mund et al, 2005;Soriano et al, 2007;Stresemann and Lyko, 2008). However, a direct link between DNA demethylation and clinical responses has not been demonstrated yet and there are currently no established DNA methylation biomarkers that accurately predict patient responses (Fandy et al, 2009). This remains as an important challenge that is related to the complex mode of action of azanucleosides (see below) and that will have to be addressed in future studies to firmly establish clinical proof-of-concept for epigenetic therapy with these drugs.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies

Cited by 266 publications

References 43 publications

Fas expression at diagnosis as a biomarker of azacitidine activity in high-risk MDS and secondary AML

Fas expression at diagnosis as a biomarker of azacitidine activity in high-risk MDS and secondary AML

Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities

Epigenetic cancer therapy: rationales, targets and drugs

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