Author ORCID Identifier
0000-0003-1738-7734
Date of Graduation
8-2023
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Dr. Zhiqiang An
Committee Member
Dr. Anil Sood
Committee Member
Dr. Kyoji Tsuchikama
Committee Member
Dr. Momoko Yoshimoto
Committee Member
Dr. Ningyan Zhang
Abstract
High-grade serous ovarian carcinoma (HGSC) is an aggressive subtype of epithelial ovarian carcinoma (EOC) and remains the most lethal gynecologic cancer. Angiogenesis is a vital function for both wound healing and oxygen homeostasis and is one of the hallmarks of cancer in solid tumors. To combat the formation of tumors, an anti-VEGF drug, bevacizumab, is used to starve tumors of blood that provide essential nutrients. While platinum-taxane doublet therapy in addition to cytoreductive surgery has been the gold standard treatment for patients with ovarian cancer, greater than 70% of patients will develop relapsed disease and be burdened with a terminal condition. Consequently, there is an urgent need to identify novel drug targets that specifically mediate disease progression, but not normal biological processes, is urgently needed.
Microseminoprotein (MSMP), found to be significantly upregulated in patients with platinum-resistant ovarian cancer, provides a potential escape mechanism against anti-angiogenic therapy. Pre-clinical studies indicate that inhibiting MSMP in adaptive-resistant ovarian tumors combined with anti-angiogenic therapy can overcome adaptive resistance to anti-VEGF antibody-based therapy. Due to the high specificity of their targets and safety profiles, antibodies are a proven and fast-growing drug modality for human diseases. The objective of this study was to use the diverse scFv phage library in our laboratory to develop antibody probes. These will help us investigate the extent MSMP has on cancer biology.
Our work involved generating a panel of six monoclonal antibodies (mAbs) against MSMP, which shows potential as a drug treatment. We will present data on our antibody lead selection utilizing Octet biosensor binding kinetics, xCelligence real-time cell analysis, cell migration studies and the Tango GPCR assay for CCR2, MSMP’s cognate receptor. Results from these in vitro studies suggest that inhibiting MSMP from binding to CCR2 has potential anti-cancer properties. Specifically, it could result in a reduction in cellular proliferation and tumor endothelial cell migration in hypoxic environments. . Specifically, it could result in a reduction in cellular proliferation and tumor endothelial cell migration in hypoxic environments. If validated in animal models, the MSMP neutralizing antibodies could be developed as novel therapies for the treatment of ovarian cancer.
Keywords
adaptive resistance, angiogenesis, antibody therapy, epithelial ovarian cancer, hypoxia, msmp