DNA Methyltransferase and Histone Deacetylase Inhibitors in the Treatment of Myelodysplastic Syndromes

Griffiths, Elizabeth A.; Gore, Steven D.

doi:10.1053/j.seminhematol.2007.11.007

Cited by 192 publications

(131 citation statements)

References 40 publications

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“…Two such agents, 5-azacytidine (Vidaza) and 5-aza-2′-deoxyazacytidine (decitabine), have been approved for the therapy of neoplastic diseases (myelodysplasia, a precursor of leukemia, and chronic myelomonocytic leukemia) (33). The presumptive mechanism of action of these drugs is the activation of tumor suppressor genes or immunity-associated genes silenced in tumor cells (34,35).…”

Section: Discussionmentioning

confidence: 99%

Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells

Kim

Skora

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

578

373

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Impressive responses have been observed in patients treated with checkpoint inhibitory anti-programmed cell death-1 (PD-1) or anticytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Here we report that treatment with both anti-PD-1 and anti-CTLA-4 antibodies was unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. Cotreatment with epigenetic-modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of the tumor-bearing mice. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K inhibitor that reduced circulating MDSCs also eradicated 4T1 tumors in 80% of the mice when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.T he mammalian immune system is delicately regulated, allowing it to mount an effective attack against foreign invaders such as bacteria and viruses with minimal bystander casualties. This requires functionally redundant regulatory mechanisms to ensure safety (1-3). Cancers appear able to hijack these mechanisms to avoid immune destruction. Several of the regulatory mechanisms exploited by cancer have been identified. These include regulatory T cells (Tregs), myeloidderived suppressor cells (MDSCs), tumor-associated macrophages and neutrophils, immune checkpoint pathways, and immunosuppressive cytokines (4-8). Most recently, the checkpoints guarded by the programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) receptors have been under intense investigation because of the availability of antibodies that can inhibit their function. Recent clinical trials with anti-CTLA-4, anti-PD-1, and anti-PD-L1 monoclonal antibodies showed remarkable therapeutic responses (9-12), underscoring the idea that disruption of immune checkpoints can be therapeutically useful. However, the objective responses were observed in a minority of the treated patients and tumor types, and the reasons why certain tumors respond and others do not are mysterious. CT26 and 4T1 are among the most popular syngeneic tumor models used for assessing novel therapeutic approaches. CT26 was derived from an undifferentiated colorectal carcinoma induced in a BALB/c mouse by repeated intrarectal instillations of N-nitroso-N-methylurethan and shown to be modestly immunogenic (13,14), whereas 4T1 originated from a spontaneous mammary tumor in a BALB/c mouse (15). 4T1 is poorly immunogenic and highly metastatic, characteristics shared with advanced human cancers (16). Despite the extensive use of these tumor cell lines in cancer research, little genetic characterization is available for either of them.In the current study, we evaluated both models with respect to their responses to the immune checkpoint inhibitors alone and combined with other agents. We also determined the sequences of th...

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Section: Discussionmentioning

confidence: 99%

Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells

Kim

Skora

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

578

373

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“…1) HDAC inhibitors were combined with other epigenetic modifiers. Inhibitors of DNA methyl transferases 5-azacytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine) had increased antitumor effects when used with HDAC inhibitors [60][61][62][63][64] . Decitabine and VPA both induced apoptosis and the combination increased their effects both in vitro and in vivo 65,66 .…”

Section: Combination Of Histone Deacetylase Inhibitors With Other Thementioning

confidence: 99%

Histone deacetylase inhibitors in cancer therapy. A review

Hraběta¹,

Stiborová²,

Adam³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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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 molecular mechanisms underlying the effect of the epigenetic therapies are not completely understood, even though it is clear that the DNA methyltransferase inhibitors can induce the reexpression of methylated silenced gene products (7). After incorporation of demethylating agents into DNA, the methyltransferases are inhibited, but complete demethylation occurs only after several cycles of replication, thus accounting for time to response to these drugs (8).…”

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confidence: 99%

Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS

Follo

Finelli

Mongiorgi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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Lipid signaling pathways are involved in cell growth, differentiation, and apoptosis, and could have a role in the progression of myelodysplastic syndromes (MDS) into acute myeloid leukemia (AML). Indeed, recent studies showed that phosphoinositide-phospholipase (PI-PL)Cbeta1 mono-allelic deletion correlates with a higher risk of AML evolution. Also, a single patient treated with azacitidine, a DNA methyltransferase inhibitor currently used in MDS, displayed a direct correlation between PI-PLCbeta1 gene expression and drug responsiveness. Consequently, we hypothesized that PI-PLCbeta1 could be a target for demethylating therapy. First, we analyzed the structure of PI-PLCbeta1 gene promoter, then quantified the degree of PI-PLCbeta1 promoter methylation and gene expression in MDS patients at baseline and during azacitidine administration. Indeed, PI-PLCbeta1 mRNA increased in responder patients, along with a reduction of PI-PLCbeta1 promoter methylation. Also, the molecular response correlated to and anticipated the clinical outcome, thus suggesting that PI-PLCbeta1 gene reactivation could predict azacitidine responsiveness. Our results demonstrate not only that PI-PLCbeta1 promoter is hypermethylated in high-risk MDS patients, but also that the amount of PI-PLCbeta1 mRNA could predict the clinical response to azacitidine, therefore indicating a promising new therapeutic approach. myelodysplastic syndromes ͉ real-time PCR ͉ signal transduction ͉ inositides ͉ epigenetic therapy

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DNA Methyltransferase and Histone Deacetylase Inhibitors in the Treatment of Myelodysplastic Syndromes

Cited by 192 publications

References 40 publications

Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells

Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells

Histone deacetylase inhibitors in cancer therapy. A review

Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS

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