Author ORCID Identifier

0000-0003-4954-5696

Date of Graduation

5-2017

Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Anil K. Sood, M.D.

Committee Member

Gary E. Gallick, Ph.D.

Committee Member

Menashe Bar-Eli, Ph.D.

Committee Member

Dihua Yu, M.D., Ph.D

Committee Member

Jinsong Liu, M.D., Ph.D.

Abstract

The standard treatment for high grade serous ovarian cancer is primary cytoreductive surgery followed by adjuvant chemotherapy. Residual disease followed by surgery is associated with adverse overall and progression-free survival as well as poor response to adjuvant chemotherapy. Accurate identification of patients at high risk of residual disease will help avoid unnecessary surgeries and help in triaging these patients to neoadjuvant chemotherapy prior to interval surgical debulking. In this study, we address this clinical issue by identifying and validating molecular biomarkers that can predict the likelihood of residual disease in ovarian cancer patients. Using publically available databases and microarray datasets, we identify FABP4 and ADH1B as markers of residual disease since the high expression of these genes in tumor samples is directly associated with the incidence of residual disease. We then investigate the underlying biology of residual disease and further demonstrate that FABP4 is functionally responsible for aggressive phenotype of ovarian cancer cells that lead to residual disease in cancer patients. Using sophisticated bioinformatics techniques, several in vitro and in vivo experiments and analysis of patient samples, we explored upstream regulation of FABP4 and identified miR-409-3p as a key regulator of FABP4 expression. We further discover hypoxia as a main tumor micro-environmental factor regulating miR-409-3p and FABP4 in ovarian cancer. Using RPPA and DESI-MS imaging techniques, we explore the downstream pathways of FABP4 and discovered that FABP4 regulates several pathways associated with metastasis as well as it affects several metabolites in ovarian cancer cells. Collectively, our study provides the mechanistic understanding of residual disease biology and identifies miR-409-3p and FABP4 as potential therapeutic targets for ovarian cancer treatment.

Keywords

Ovarian cancer, Residual disease, FABP4, miR-409, Metabolomics

Available for download on Friday, May 04, 2018

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