Date

2019

Document Type

Dissertation

Degree

Doctor of Philosophy

Department

Chemistry

First Adviser

Thévenin, Damien

Abstract

The global burden of cancer is growing at an alarming pace, with the American Cancer Society projecting that there will be 21.6 million new cancer cases and 13.0 million cancer deaths in 2030. Many current FDA approved chemotherapeutics have harsh side effects due to their inability to discriminate between healthy cells and cancer cells. In recent years, there has been increasing effort to improve the selectivity of cancer therapeutics by targeting cancer biomarkers, such as overexpressed membrane receptors. However, these targeting strategies suffer from two main disadvantages: biomarkers are still expressed in healthy cells, which causes off-target toxicity, and the rapid evolution of cancer cells can lead to the loss or mutation of biomarkers, causing therapy resistance. While no specific gene mutation or chromosomal abnormality is common to all cancers, nearly all solid tumors have elevated acidosis regardless of their tissue or cellular origin. As a result, the microenvironment surrounding tumor masses are acidic (pH 6.0–6.8), in contrast to healthy tissues (pH 7.2–7.5). Acidosis may provide a universal mode of tumor targeting that is not subject to the selection of resistance.The research discussed herein is aimed at developing new methodologies to inhibit cancer cell growth by delivering therapeutics to cancer cells using the pH(Low) Insertion Peptide (pHLIP). pHLIP is a unique peptide that can selectively target cancer cells and tumors solely based on their extracellular low pH. In an acidic environment, pHLIP forms a transmembrane (TM), unidirectional helix across the membrane, in which the C-terminus inserts into the cytoplasm and the N-terminus remains in the extracellular region. Given these characteristics, our lab has previously utilized pHLIP as a tool to selectively deliver cytotoxic agents to cancer cells and tumors. Here, I will discuss our results regarding two unique approaches to kill cancer cells using pHLIP: (1) inhibiting the activity of a receptor tyrosine kinase implicated in cancer proliferation and (2) re-engaging the immune system to recognize and destroy cancer cells with an antigen-pHLIP construct.

Included in

Chemistry Commons

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