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Publication Date

2022-05-09

First Advisor

Sarah J. Moore

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Biochemistry

Keywords

Cancer, treatment, targeted therapy, mesothelin, Fn3 protein, Cancer overview, traditional cancer treatment, novel cancer treatment

Abstract

Mesothelin (MSLN) is a membrane-bound polypeptide overexpressed on the cell surface in multiple cancers, including mesothelioma, ovarian, breast, lung, and pancreatic cancer. MSLN promotes tumor proliferation, therapeutic resistance, invasion, and metastasis, resulting in the delayed prognosis of cancer through mechanisms that remain inadequately understood. While cancer cells rely on MSLN for survival, growth, and angiogenesis, normal cells survive and thrive without MSLN. The selective expression in tumor cells makes MSLN an excellent biomarker for targeted therapy. Molecules that target mesothelin and inhibit it from contributing to tumor progression can potentially be used as targeted therapy. Although none of the anti-MSLN treatments have been FDA-approved for regular clinical use, numerous mesothelin-targeting therapeutic agents are in ongoing research and clinical development. This project presents the development and assessment of a mesothelin-targeting protein based on the fibronectin type- III non-antibody protein scaffold (Fn3). The Fn3 protein could be applied where immunotherapy and traditional chemotherapy have limitations and improve the overall anti-cancer efficacy. This thesis demonstrated that engineered protein variant Fn3 5.3.2 binds mesothelin with high affinity and selectively initiates apoptosis in tumor cells expressing MSLN. However, the specific apoptosis-inducing mechanism remains to be determined. Further, imaging the cellular internalization process of Fn3 protein by confocal microscopy could reveal critical information on the apoptosis-inducing pathways.

Rights

©2022 Florence Yunan Qian. Access limited to the Smith College community and other researchers while on campus. Smith College community members also may access from off-campus using a Smith College log-in. Other off-campus researchers may request a copy through Interlibrary Loan for personal use.

Language

English

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