ORCID

http://orcid.org/0000-0002-9229-3378

Date of Award

Spring 5-15-2023

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

High-Grade Serous Ovarian Cancer (HGSC) is a highly metastatic cancer with the majority of patients presenting in advanced stages. Currently there are limited targeted treatment options for patients, especially for women with high metastatic tumor burdens. In order to improve patient outcomes, we have aimed to identify and characterize novel targets of metastasis utilizing sequencing from patient tumors and a functional genomic screen. First, we identified genetic alterations of metastasis and short survival by characterizing the genomic and transcriptomic alterations of primary and metastatic tumors in HGSC patients from 23 short-term survivors (overall survival (OS) <3.5 years) and 16 long-term survivors (OS >5 years). We compared somatic mutations, copy number alternations, mutational burdens, differential expression, immune cell fractions, and gene fusion predictions between the primary and metastatic tumors of the ST and LT survival groups. From this project we identified a TP53 R273H mutation, which may have a gain-of-function in ovarian cancer, suggested from evidence in triple negative breast cancer. We aimed to determine if this mutation can be targetable with PARP inhibitor combination treatments and if this mutation is gain-of-function in ovarian cancer cell lines. Third, we performed a siRNA functional genomic screen on 719 kinases in an attachment assay utilizing a collagen fibronectin matrix plated with primary ovarian fibroblasts and GFP-labeled ovarian cancer cell lines. From this initial screen, we have identified 4 candidate kinases to validate. Candidate kinases were validated by siRNA knock-down in ovarian cancer cell lines and assessed on their ability to migrate in a wound-healing assay.

Language

English (en)

Chair and Committee

Jason Weber Katherine Fuh

Committee Members

John Edwards, Christopher Maher, Graham Colditz,

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