ORCID

0000-0002-9597-9252

Date of Award

4-26-2024

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

Ovarian cancer is the 5th leading cause of cancer death in women with a 5-year survival rate around 30%. Up to 80% of ovarian cancer patients experience disease recurrence and the majority of those cases are resistant to treatment. Therefore, there is a need to understand the mechanisms of chemo-resistance in order to create new therapies and increase patient survival. To accomplish this, I first developed novel, chemo-resistant, syngeneic mouse ovarian cancer cell lines by serial passaging ovarian cancer cells through mice and treating with increasing doses of chemotherapy. These cell lines fill a need in the field for matched chemo-sensitive (CNAS) and chemo-resistant (CHRP5) ovarian cancer cell lines that can be used in immunocompetent mice. After developing these cell lines, I then performed whole exome RNA sequencing comparing CNAS to CHRP5 gene expression. Differential expression analysis revealed many genes that are differentially regulated in acquired resistance such as ABCG2, a chemo efflux protein, and GMPNB, a glycoprotein. We confirmed differential expression of these genes but did not experiment further. We identified DDR2 as a potentially important part of acquired chemo-resistance using patient data correlating high DDR2 expression and reduced response to chemotherapy. We then used both in vitro and in vivo models to determine if DDR2 depletion can re-sensitize tumor cells to chemotherapy using CNAS and CHRP5 cells I developed, in addition to other human immortalized cell line models. We found that neither genetic nor pharmacological inhibition of DDR2 changed tumor response to chemotherapy. In tandem, we also investigated the effectiveness of novel small molecule inhibitor (AVB-500) of the receptor tyrosine kinase, AXL. We found that treatment with AVB-500 in addition to chemotherapy or bevacizumab treatment for mice injected with multiple cancer cell models reduced tumor burden in vivo. Overall, we filled a need for a new tool in acquired chemo-resistance experiments and determined that DDR2 is not necessary or sufficient to create resistance to chemotherapy.

Language

English (en)

Chair and Committee

Gregory Longmore

Download

Share

COinS