Date of Award

Fall 2021

Project Type

Thesis

Program or Major

Biochemistry

Degree Name

Master of Science

First Advisor

Sarah Walker

Second Advisor

Sarah Walker

Third Advisor

Paul Tsang

Abstract

According to the American Cancer Society, approximately 21,410 women will receive a diagnosis of ovarian cancer, and 13,770 women will die from ovarian cancer in 2021. Typically, ovarian cancer is not diagnosed until it has reached stage III/IV in its progression. By later stages of disease, an ovarian cancer tumor has migrated to the peritoneum, existing either in single cell or spheroid form, and resulting in inflammation and buildup of ascites fluid, and metastasis of secondary tumors. Ascites fluid is comprised of many different secreted extracellular matrix (ECM) molecules, proteases and cytokines. The cytokine IL-6 is abundant in ascites fluid and can bind to its receptor, signaling the JAK/STAT3 cascade, activating STAT3 and promoting transcription of target genes. Constitutive activation of STAT3 has been found in the ascites fluid and ascites-derived ovarian cancer cells of ovarian cancer patients and correlates with aggressive tumor growth and metastasis. Cisplatin is a chemotherapeutic drug that is typically used as a first-line treatment of ovarian cancer. Over time, ovarian cancer evolves to resist the DNA damaging effects of cisplatin by evading apoptosis. Another mechanism by which ovarian cancer cells develop chemoresistance is through the Epithelial-to-Mesenchymal Transition (EMT). Aberrant STAT3 activity in ovarian cancer has been implicated in both evasion of apoptosis and EMT, making STAT3 an attractive target for understanding chemotherapy resistance in ovarian cancer. To study STAT3 in cisplatin resistant ovarian cancer, a clinically relevant model is required. Chowanadasi et al. adapted an ovarian cancer cell line that closely modeled the heterogeneity of high grade serous ovarian cancer (OVCAR-8) to resist cisplatin treatment. The researchers then ran gene wide expression profiles on both OVCAR-8 cisplatin sensitive (OVCAR-8CS) and OVCAR-8 cisplatin resistant (OVCAR-8CR) cells grown in 3D (spheroids). Over three thousand genes were found to be differentially expressed between the paired cell line, many of which were possible STAT3 targets. I hypothesized that STAT3 plays a role in cisplatin resistance in ovarian cancer and developed two goals to investigate this role. The first goal was to look at STAT3 target genes involved in either EMT or evasion of apoptosis to assess if modulation of these genes would result in re-sensitization of OVCAR-8CR to cisplatin. The second goal was to treat OVCAR-8CR spheroids with drugs identified as STAT3 inhibitors, alone and in combination with cisplatin, to determine if re-sensitization of OVCAR-8CR to cisplatin could be accomplished. None of the four STAT3 target genes chosen re-sensitized OVCAR-8CR spheroids to cisplatin. While this was disappointing, many more STAT3 target genes have yet to be investigated for their role in cisplatin resistance; therefore, it is still possible that STAT3 is playing a role in cisplatin resistance. While results of the first goal were disappointing, results of the second goal were successful. Five STAT3 inhibitors were tested (nifuroxazide, atovaquone, simvastatin, lovastatin and atorvastatin) and three, simvastatin, lovastatin and atorvastatin, have strong preliminary results of reducing OVCAR-8CR growth. Further research is needed into statins as ovarian cancer drugs, but their apparent effectiveness as STAT3 inhibitors in reducing OVCAR-8CR spheroid growth, highlights the pivotal role STAT3 is playing in cisplatin resistant ovarian cancer.

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