Evaluating the Ceramide Nanoliposome as a Therapy for Head and Neck Squamous Cell Carcinoma - Circumventing Resistance, Characterizing Death, Utilizing Dual Therapies, and Manipulating Metabolism
Shaw, Jeremy, Experimental Pathology - School of Medicine, University of Virginia
Kester, Mark, MD-PHAR Pharmacology, University of Virginia
Head and Neck Squamous Cell Carcinoma (HNSCC) is the seventh most deadly cancer in the world. While traditional therapies are highly morbid, there have been only a few new systemic treatments developed in the last few decades, and these benefit only a small population of patients. The anti-cancer signaling sphingolipid ceramide has shown promise as a therapeutic in many cancer models including preliminary work in HNSCC. The ceramide nanoliposome (CNL) is a nanoscale, therapeutic ceramide-delivery vehicle currently in Phase I clinical trials for treating advanced solid tumors. Thus, the thesis seeks to evaluate the CNL as a potential therapeutic for HNSCC. This is accomplished by exploring methods to circumvent resistance (Chapter 2), identify novel markers of non-canonical cell death (Chapter 3), utilize synergistic dual therapeutic approaches with previously failed EGFR inhibitors (Chapter 4), and manipulate sphingolipid metabolism (Chapter 5). These studies elucidate a myriad of signaling pathways as well as specific druggable targets that can be manipulated to enhance therapeutic efficacy of CNL or other ceramide-based therapies for treatment of HNSCC.
PHD (Doctor of Philosophy)
Ceramide, Ceramide Nanoliposome (CNL), Sphingolipids, Head and Neck Squamous Cell Carcinoma (HNSCC), Autophagy / Mitophagy, Lysosomes, Cell Death, Epidermal Growth Factor Receptor (EGFR), Early Growth Response 1 (EGR-1), Sphingolipid Metabolism, Glucosylceramide Synthase (GCS), Hypoxia, Multiple Sclerosis (MS), Cannabinoids
NIH/NCI 2 T32 CA009109
All rights reserved (no additional license for public reuse)