Platinum resistance in ovarian cancer is associated with accumulation of epigenetic changes leading to transcriptional silencing of tumor suppressor and chemo-responsiveness-associated genes. A clinical trial designed and conducted previously demonstrated that methylome-targeted interventions reverse platinum resistance and induce clinical responses. Building upon this work, we propose to extend the ovarian cancer epigenome analysis by using MBDCap-sequencing and bioinformatics and to test the effects of SGI-110, a novel DNA methyl transferase inhibitor (DNMTI). The hypothesis to be tested is that platinum resistance in ovarian cancer is uniquely reflected in DNA methylation changes and can be reversed by DNMTI. To address this hypothesis, tumor and plasma samples collected from an ongoing randomized phase II clinical trial comparing SGI-110 and carboplatin to FDA-approved strategies for platinum-resistant ovarian cancer will be analyzed. Clinical specimens from ~100 patients will be available for analysis.
Three aims are proposed.
For Aim 1, DNMTI-induced changes in the ovarian cancer methylome will be measured by using MethylCap-seq on tumor biopsies obtained before and after SGI-110. The objective of this Aim is to investigate whether SGI-110 induces global methylome changes affecting networks of genes associated with chemo-responsiveness. The objective of Aim 2 is to determine whether DNMT expression levels differ in recurrent vs. primary tumors and whether expression levels at enrollment or changes induced by DNMTIs correlate with clinical benefit.
For Aim 3, the objective is to determine whether specific genes methylation levels at enrollment and changes induced by DNMTIs correlate with clinical benefit. This project will identify critical DNA methylation events that govern the development of platinum resistance. The proposed studies are highly innovative based on the use of state-of- the-art MBDCap-Seq and bioinformatics applied to a question of high clinical relevance. Successful completion of the correlative work integrated in this trial will identify predictive markers of response to methylome-targeting strategies. This study will bring epigenetic interventions to the forefront of therapy for ovarian cancer impacting treatment strategies and outcomes for this deadly cancer. Successful completion of this study will move forward the field of epigenome-targeted therapy for solid tumors and will provide key information for biologically- directed future design of phase III trials.

Public Health Relevance

Women with advanced stage ovarian cancer usually relapse after initial treatment, develop platinum-resistance, and succumb to the disease. This project will identify the critical epigenetic (DNA methylation) events that govern the development of platinum resistance, which can then serve as predictive markers of response to epigenetic-targeting strategies. The successful completion of this study will bring epigenetic strategies to the forefront ovarian cancer treatment, ultimately making an impact on the outcome of this deadly cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA182832-01
Application #
8627405
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Song, Min-Kyung H
Project Start
2014-02-14
Project End
2019-01-31
Budget Start
2014-02-14
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$323,700
Indirect Cost
$116,200
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
de Leon, Maria; Cardenas, Horacio; Vieth, Edyta et al. (2016) Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer. Gynecol Oncol 142:539-47
Cardenas, Horacio; Zhao, Janice; Vieth, Edyta et al. (2016) EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells. Oncotarget :
Özeş, A R; Miller, D F; Özeş, O N et al. (2016) NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer. Oncogene :
Benson, Eric A; Skaar, Todd C; Liu, Yunlong et al. (2015) Carboplatin with Decitabine Therapy, in Recurrent Platinum Resistant Ovarian Cancer, Alters Circulating miRNAs Concentrations: A Pilot Study. PLoS One 10:e0141279
Cooley, Megan; Fang, Pingping; Fang, Fang et al. (2015) Molecular determinants of chemotherapy resistance in ovarian cancer. Pharmacogenomics 16:1763-7
Mitra, Anirban K; Davis, David A; Tomar, Sunil et al. (2015) In vivo tumor growth of high-grade serous ovarian cancer cell lines. Gynecol Oncol 138:372-7
Tang, Jessica; Fang, Fang; Miller, Dave F et al. (2015) Global DNA methylation profiling technologies and the ovarian cancer methylome. Methods Mol Biol 1238:653-75
Bowtell, David D; Böhm, Steffen; Ahmed, Ahmed A et al. (2015) Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer 15:668-79
Wang, Yinu; Cardenas, Horacio; Fang, Fang et al. (2014) Epigenetic targeting of ovarian cancer stem cells. Cancer Res 74:4922-36
Fang, Fang; Munck, Joanne; Tang, Jessica et al. (2014) The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res 20:6504-16