Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Garcia‐Manero, Guillermo; Tambaro, Francesco Paolo; Bekele, N.; Yang, Hui; Ravandi, Farhad; Jabbour, Elias; Borthakur, Gautam; Kadia, Tapan M.; Konopleva, Marina; Faderl, Stefan; Cortes, Jorge; Brandt, Mark; Hu, Yumin; McCue, Deborah; Newsome, Willie; Pierce, Sherry; Lima, Marcos J.G. de; Kantarjian, Hagop M.

doi:10.1200/jco.2011.38.3265

Cited by 160 publications

(107 citation statements)

References 22 publications

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“…Our results indicate that HDACi target the bone marrow microenvironment in addition to directly killing AML cells, which may help explain their efficacy in AML combination therapy (11,13,14). Disordered epigenetics within AML cells originally suggested that HDACi may be useful for treating AML (40,41).…”

Section: Discussionmentioning

confidence: 81%

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Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

Kremer

Dudakovic

Hess

et al. 2015

Journal of Biological Chemistry

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Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8, 10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast-mediated protection of AML cells. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co-cultured AML cells from SDF-1-induced apoptosis. HDACi prominently upregulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase-1␣ (PP1␣) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1␣ or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1␣-TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis.For decades, research into drug treatments for acute myeloid leukemia (AML) 2 has focused on directly targeting AML cells for destruction. Even though complete remission rates have improved, relapse remains a problem in the majority of patients with this disease. The bone marrow microenvironment has gained attention as a protective environment that promotes survival of AML stem cells, despite the killing of the majority of AML cells by standard chemotherapeutics (1-5). The endosteum, the tissue between the bone marrow and ossified surface, has been particularly implicated as a protective niche because AML stem cells are localized to this region following chemotherapeutics (6, 7). Within the endosteal niche, cells of the osteoblast (bone-generating) lineage have been identified as critical mediators of AML cell survival in the bone marrow (4, 8). Transgenic mice expressing activated ␤-catenin specifically in osteoblasts develop myeloid malignancy, consistent with the idea that osteoblasts promote this disease (9). Unfortunately, the molecular mechanisms responsible for osteoblast-mediated protection of AML cells are incompletely understood. This lack of knowledge prevents effective therapeutic manipulation of the bone marrow microenvironment as a way to enhance targeting of AML cells within the bone marrow. We...

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Section: Discussionmentioning

confidence: 81%

“…These drugs globally regulate gene expression via increasing acetylation of histones, proteins that control chromatin accessibility to transcription factors. In AML, HDACi have shown efficacy in combination with standard chemotherapeutics such as cytarabine (11)(12)(13)(14) …”

mentioning

confidence: 99%

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

Kremer

Dudakovic

Hess

et al. 2015

Journal of Biological Chemistry

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“…The combination of vorinostat with idarubicin and cytarabine had synergistic activity that was maximal when vorinostat preceded cytarabine. In a phase II trial, the response rate of 85% of the combination was superior to that of idarubicin and cytarabine alone; notably, there were responses in all patients with FLT3-ITD mutations 81,82 . Phase II trials using administration of vorinostat in refractory cutaneous T-cell lymphoma patients showed an objective response in nearly 30% of these patients 30,83 .…”

Section: Clinical Studies and Registered Drugsmentioning

confidence: 97%

Histone deacetylase inhibitors in cancer therapy. A review

Hraběta¹,

Stiborová²,

Adam³

et al. 2014

BIOMED PAP

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a Background. Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies. Results. Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Conclusions. Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

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“…The addition of vorinostat to standard induction therapy with cytarabine and idarubicin was recently evaluated in a phase II trial that included 68 patients with AML. The investigators found no vorinostatrelated toxicity and therefore will pursue a randomized trial investigating the efficacy of adding vorinostat to standard induction versus standard therapy alone [30].…”

Section: Epigenetic Modulatorsmentioning

confidence: 99%

Novel agents in acute myeloid leukemia

Ungewickell

Medeiros

2012

Int J Hematol

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Although complete remissions can be achieved in most patients younger than 60 years of age with untreated acute myeloid leukemia (AML), only 30-40 % of patients remain long-term survivors. Furthermore, longterm survivors represent only 10-15 % of all AML patients older than 60 years of age and \10 % of all patients with relapsed AML. The development of new treatments for AML is therefore needed. Novel therapies should target specific mechanisms and pathways implicated in the development and maintenance of AML, should strive to have better tolerability than conventional combination chemotherapy, be associated with improved quality of life and minimize utilization of health care resources. In this manuscript, we discuss the role of epigenetic regulators and immunomodulatory agents in the treatment of AML. Also, we review the data on inhibitors of protein homeostasis and its synergistic effect to DNA methyltransferase inhibitors, the potential role for inhibitors of heat shock proteins and the mitotic machinery and a novel formulation of conventional chemotherapeutic agents given at a fixed molar concentration. Finally, we briefly share our views on optimal clinical trial design and patient selection for future studies in AML.

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Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Cited by 160 publications

References 22 publications

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

Histone deacetylase inhibitors in cancer therapy. A review

Novel agents in acute myeloid leukemia

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