2015 Keystone Conf: DNA Methylome Alterations in Platinum Resistant Ovarian Cancer Tumors

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Summary

Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in ovarian cancer. An ongoing phase I/II multi-institutional clinical trial uses the novel DNA methyl transferase (DNMT) inhibitor SGI-110 to resensitize recurrent platinum resistant ovarian cancer to carboplatin.

Tumor biopsies or malignant ascites were collected at baseline and after two cycles of SGI-110 administered daily for 5 days in low dose (30mg/m2). The goal of the current study was to analyze
global DNA methylation profiles of platinum resistant tumors and compare them to the methylome of untreated, platinum-sensitive ovarian tumors. LINE1 methylation and promoter methylation of
selected genes (MAGE-A2, MAGE-A3, MAGE-A11, NY-ESO, RASSF1, MLH1, and HOXA11) were quantified by pyrosequencing before and after SGI-110 treatment (n=12 paired samples).

Epigenetic profiling using the Infinium HumanMethylation450 BeadChip (HM450) revealed extensive methylation changes when comparing recurrent platinum resistant ovarian tumors (n=42) to
primary, untreated ovarian cancer specimens analyzed as part of the TCGA project (n=10). Six hundred and four promoters were significantly differentially methylated (adjusted p<0.05, absolute methylation changes β>0.2), among which, 498 and 106 were hypermethylated or hypomethylated respectively in recurrent platinum resistant ovarian tumors. DNMT1, 3A, and 3B mRNA levels in the tumors were highly variable (n=19). Analysis of a limited number of paired samples (n=7) revealed no significant changes in global methylation or in DNMT expression levels induced by  treatment with SGI-110 (adjusted p>0.05). However, the DNMT inhibitor induced significant methylome alterations in selected patients. Significant hypomethylation of MAGE-A3 and
MAGE–A11 promoters (p<0.05) was detected. Correlations between methylation changes and clinical outcomes are being explored.

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2015 Keystone Conf: DNA Methylome Alterations in Platinum Resistant Ovarian Cancer Tumors

2015 ASCPT: Systems Pharmacology Modeling of Decitabine and SGI-110

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Summary

Acute myeloid leukemia (AML) is a tumor associated with myeloid line of blood cells, characterized by the abnormal rapid proliferation of white blood cells in the bone marrow. The most common approach for AML treatment is the reduction of abnormal cell proliferation rate which can be achieved by targeting the key stages of the cell cycle.

Decitabine is a well characterized hypomethylating agent (HMA), which is incorporated into DNA during the S-phase of cell cycle, inhibits methylation of antitumor genes and induces G2/M arrest. However, it has a very short half-life (15-35 min) after IV infusion due to rapid degradation by cytidine deaminase. SGI-110, a 2nd generation HMA was designed to increase the in vivo xposure/potential efficacy of its active metabolite decitabine. The aim of this effort was to explore how changes in exposure window of decitabine affect DNA demethylation and tumor cell proliferation in AML patients.

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2015 ASCPT: Systems Pharmacology Modeling of Decitabine and SGI-110