DOI
https://doi.org/10.25772/Q1ZF-3Q75
Defense Date
2011
Document Type
Thesis
Degree Name
Master of Science
Department
Human Genetics
First Advisor
SHAWN HOLT
Abstract
Molecular chaperones, commonly known as heat shock proteins (HSPs), are essential for mammalian cells to maintain homeostasis, and HSPs function by inducing an ATPase-coupled structural change, followed by interactions with diverse co-chaperones and over 200 client proteins implicated in many critical signaling networks. These highly expressed HSPs participate in the onset and progression of several human diseases including cancer, and their connection with tumorigenesis has facilitated research and clinical trials related to targeting HSPs as a novel anti-tumor therapy. The predominant mechanism of chaperone inhibition is through either disruption of the HSP association with client protein or an altered binding state that ultimately leads to proteasome-mediated degradation. Importantly, chaperone inhibition results in the degradation of several client proteins that play critical roles in many of the pathways known as the Hallmarks of Cancer, such as proliferation, angiogenesis, invasion, metastasis, and drug resistance. Here, we discuss: (1) the current knowledge of HSPs, particularly studies related to Hsp90-targeted cancer therapy, (2) the targeting of Hsp90-mediated signaling interactions to prevent emergence of core Hallmarks of Cancer, (3) the recent progression of Hsp90 inhibitors in clinical trials. Finally, we propose combinatorial therapy, additional inhibitor discovery, and location-specific inhibition of HSPs as necessary next steps in chaperone-targeted research relevant to cancer therapy.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
July 2011