Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts

Abstract

The mechanism of clinical action for the FDA approved hypomethylating drugs azacitidine and decitabine remains unresolved and in this context the potential immunomodulatory effect of these agents on leukemic cells is an area of active investigation. Induced expression of methylated Cancer Testis Antigen (CTA) genes has been demonstrated in leukemic cell lines following exposure to hypomethylating drugs in vitro. SGI-110 is a novel hypomethylating dinucleotide with prolonged in vivo exposure and clinical activity in patients with MDS and AML. We demonstrate that this agent, like decitabine, produces robust re-expression of the CTAs NY-ESO-1 and MAGE-A, both in vitro and in leukemia-bearing AML xenografts. Upregulation of these genes in vitro was sufficient to induce cytotoxicity by HLA-compatible CD8+ T-cells specific for NY-ESO-1, a well-recognized and immunogenic CTA. Additionally, exposure to SGI-110 enhances MHC class I and co-stimulatory molecule expression, potentially contributing to recognition of CTAs. SGI-110, like the parent compound decitabine, induces expression of CTAs and might modulate immune recognition of myeloid malignancy.

Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy

“…1; refs. [19][20][21][22]. Although the immunomodulatory activities of DNMTi and of HDACi are frequently overlapping, some preferential tropism of the 2 drug classes can be observed, essentially depending on the prevalent molecular mechanism regulating the specific target molecules.…”

“…Of relevance, long-lasting phenotypic immunomodulation appears to be essentially restricted to treatments with DNMTi through their ability to generate heritable changes in gene expression (23). The clinical appeal of these findings relays on the ability of the phenotypic modulations induced by epigenetic compounds to translate into an upregulated functional recognition and killing of tumor cells by antigen-specific CTL, both in vitro and in vivo (11,20). In addition, HDACi were found particularly effective in inducing a stress response on tumor cells, which led to the upregulated expression on their surface of the NKG2D ligands (MICA, MICB, and ULBPs) and to an increased killing of tumor cells by NK cells ( Fig.…”

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

“…SGI-110 displays desirable pharmacokinetics and metabolic stability, and is currently in Phase II clinical trials for patients with MDS and AML (Yoo et al, 2007;Chuang et al, 2010;Singh et al, 2013;Tanq et al, 2013;Fang et al, 2014;Srivastava et al, 2014;Tellez et al, 2014). RX-3117, another nucleoside analogue, was designed and developed based on cyclopentenyl-cytosine derivatives by Rexahn, a clinical stage biopharmaceutical company.…”

Epigenetic therapy in gastrointestinal cancer: the right combination

“…These drugs are designed to be more specific in targeting tumor DNMTs while being less rapidly degraded. These include the small molecules hydralazine, already in use for many years as an antihypertensive, and zebularine, a nucleoside analog DNMT inhibitor that also inhibits cytidine deaminase [Zhou et al 2002]; MG98, an antisense oligonucleotide that binds directly to DNMT mRNA to prevent its translation [Stewart et al 2003]; and SGI-110, a complex of DAC with deoxyguanosine which causes resistance to degradation by cytidine deaminase [Srivastava et al 2014].…”