Document Type

Thesis

Publication Date

5-10-2019

Disciplines

Amino Acids, Peptides, and Proteins | Obstetrics and Gynecology | Oncology | Therapeutics

Advisor

Philip Chu, Biology

Abstract

Endometrial cancer is the most common gynecological malignancy and accounts for 6% of all cancers in women. In 2018, there were an estimated 63,280 new cases of endometrial cancer resulting in 11,350 deaths. In advanced stages, aggressive forms of endometrial cancer are able to invade the peritoneum and metastasize to the omentum and bowel. Shridhar et al. have identified leucine rich repeat containing 15 (LRRC15), a protein involved in cell adhesion and interactions with the extracellular matrix (ECM), as a potential therapeutic target due to its significantly higher expression in ovarian cancer tumors that have metastasized to the omentum and bowel when compared to their matched primary tumor counterparts. Additionally, Shridharet al. have shown that LRRC15 is capable of associating directly with β1-integrin and promotes invasion and metastasis through the activation of focal adhesion kinase (FAK) in ovarian cancer. In this study, knockdown of LRRC15 in endometrial cancer cell lines lowered the expression of proteins within the FAK signaling pathway, decreased cancer cell adhesion, and decreased cell migration in vitro. Conversely, induced overexpression of LRRC15 led to an increase in expression of proteins in the FAK pathway and an increase in cell adhesion. Treatment of endometrial cancer cell lines with the therapeutic agent ABBV-085, a drug antibody conjugate which targets cells expressing LRRC15, was tested in vitro and demonstrated high specificity compared to the control with an IC50 between 0.1-1.0 nM. Overall, our results from LRRC15 knockdown and ABBV-085 treatment demonstrate that targeting LRRC15 may be therapeutically beneficial in endometrial cancer.

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