Date of Graduation

5-2016

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Kwong-Kwok Wong, Ph.D.

Committee Member

Robert C. Bast, Jr., M.D.

Committee Member

Ann M. Killary, Ph.D.

Committee Member

Samuel C. Mok, Ph.D.

Committee Member

Rosemarie E. Schmandt, Ph.D.

Committee Member

Zahid H. Siddik, Ph.D.

Abstract

Growth Differentiation Factor 15 (GDF15) is induced in situations such as stress, inflammation, treatment with non-steroidal anti-inflammatory drugs, as well as other therapeutic agents. As a secreted protein, GDF15 is seen as a potential biomarker in several types of cancer as well as in other diseases such as cardiovascular diseases, diabetes, and rheumatoid arthritis. In ovarian cancer, high GDF15 serum levels correspond to poor survival. It has further been shown to be expressed at higher levels in serum in ovarian cancer patients post-chemotherapy than pre-chemotherapy.

The overall 5-year survival for ovarian cancer is 46%, as a result of late diagnosis when treatment is mostly ineffective. Following initial treatment, 50-75% of patients will develop chemoresistance. Therefore, there is a great interest in identifying markers and therapeutic targets to improve treatment outcome. In this study, we aimed to determine the role that GDF15 plays in the chemoresponse to cisplatin in ovarian cancer. A microarray study identified GDF15 as being among the most highly induced genes following cisplatin treatment of an ovarian cancer cell line. This observation was further verified both in vitro and in vivo. We also found GDF15 induction by platinum agents to be p53 dependent. In addition, in vivo studies of a mouse orthotopic model revealed that GDF15 knockdown tumors were larger than control tumors. The tumors in which GDF15 had been knocked down were smaller following cisplatin treatment. Furthermore, in vivo tumors formed with A2780 ovarian cancer cells in which GDF15 expression was suppressed, demonstrated a reduced percentage of stromal cells compared to tumors formed with control A2780 cells. The stromal percentage of the GDF15 knockdown tumors did not change following cisplatin treatment unlike the control tumors. This study shows for the first time that GDF15 affects tumor composition. In addition, RPPA and RNA-seq was conducted on the mouse tumors to identify downstream targets of GDF15.

In summary, this study showed that induction of GDF15 by platinum agents is p53 dependent. This study further showed the effect GDF15 has in ovarian cancer, specifically the tumor composition. This study suggests that targeting GDF15 could be beneficial for patients with p53 wild type ovarian tumors that are often resistant to standard platinum-taxane chemotherapy. Further studies to identify the GDF15 receptor and downstream pathways are necessary.

Keywords

ovarian cancer, GDF15, cisplatin, p53

Available for download on Wednesday, May 03, 2017

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