Novel Tumor Glycan Targeted Therapeutic Approaches To Inhibit Ovarian Cancer Progression

Authors

Rhyisa Armbrister, Florida International UniversityFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biochemistry

First Advisor's Name

Yuan Liu

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Charles Dimitroff

Second Advisor's Committee Title

Committee Member

Third Advisor's Name

Kevin Chandler

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Lidia Kos

Fourth Advisor's Committee Title

Committee Member

Keywords

Ovarian Cancer, Cancer, Glycobiology, Glycans, PROTAC, ScFv, NOTCH, RFNG

Date of Defense

3-15-2023

Abstract

Ovarian cancer is an aggressive gynecological cancer that usually goes undetected until it becomes a progressive and metastatic disease, often leading to death. Early-stage patients lack noticeable symptoms. Currently, there are no early screening tests or effective treatments. To address challenging problems, we sought to explore ovarian tumor-specific glycosylation patterns as targets for the development of cancer-specific diagnostic and therapeutic applications. We leveraged a unique bisecting asparagine (N)-linked glycosylation feature on ovarian cancer cells to generate a single chain variable fragment-9 (scFvC9)- Proteolysis Targeting Chimera (PROTAC) system to specifically bind bisecting N- linked glycoproteins on ovarian cancer cells. Our results demonstrated the feasibility of the scFvC9-PROTAC system to hijack the ubiquitin-proteasome pathway and degrade bisecting N-linked glycoproteins. The results also revealed that the scFvC9-PROTAC molecule-induced degradation of internalized bisecting N-linked glycoproteins, reduced the viability of ovarian cancer cells and preferentially bound to an ovarian tumor-initiating cell (TIC) population. Furthermore, we found that the scFvC9-PROTAC was internalized into ovarian cancer cells through the endosome/lysosome pathway. Moreover, we explored the critical roles of radical fringe glycosyltransferase (RFNG)-mediated glycosylation in modulating ovarian cancer progression. The results showed that RFNG promoted ovarian cancer cell proliferation and tumor growth by activating the Notch signaling pathway. Together these dissertation studies 1) Investigated a unique scFvC9-PROTAC system that can potentially be used as a novel therapeutic approach to target ovarian cancer cells and 2) Provided new insights into the pro-tumorigenic role of RFNG and its potential as a novel target for ovarian cancer treatment. This dissertation research highlights the significance of ovarian cancer-associated glycosylation and its promise for improving ovarian cancer prevention, diagnosis, and therapy.

Identifier

FIDC011011

ORCID

https://orcid.org/0000-0001-6595-7020

Recommended Citation

Armbrister, Rhyisa, "Novel Tumor Glycan Targeted Therapeutic Approaches To Inhibit Ovarian Cancer Progression" (2023). FIU Electronic Theses and Dissertations. 5312.
https://digitalcommons.fiu.edu/etd/5312