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Title:Development of PAC-1 as a privileged agent for combination chemotherapy
Author(s):Botham, Rachel C
Director of Research:Hergenrother, Paul J
Doctoral Committee Chair(s):Hergenrother, Paul J
Doctoral Committee Member(s):van der Donk, Wilfred A; Mitchell, Douglas A; Fan, Timothy M
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):caspase
cancer
Abstract:Elucidation of the molecular mechanisms of cancers has enabled the development of molecularly targeted chemotherapeutics capable of exploiting cancer-specific cellular alterations. Small-molecule activation of procaspase-3 represents a particularly promising opportunity, based upon its determinant role in the execution of apoptosis and its widespread over-expression across many diverse cancer types. PAC-1 is a small-molecule that facilitates procaspase-3 activation by relieving physiological zinc- mediated inhibition of auto-proteolytic activation. Activation of procaspase-3 by PAC-1 was previously demonstrated to induce apoptosis in cancer cells and be efficacious in select murine tumor models. Described herein is the evaluation of PAC-1 in combination with diverse chemotherapeutics, and leveraged for the treatment of challenging cancers. Concurrent external development of a second class of mechanistically-distinct procaspase-3 activating compounds, enabled a proof-of-concept evaluation of dual targeting of a single protein with small-molecule activators. Synergistic enhancement in protein activity, signaling pathway activation and in vivo efficacy were observed. This substantiated the hypothesis that when orthogonal mechanisms of protein activation were possible, that dramatic enhancements in biologic effect could be observed, thereby establishing a novel strategy for combining molecularly targeted chemotherapeutics. Building upon the success of dual targeting of executioner caspases for enhanced apoptotic effect, PAC-1 was investigated as a method to broadly enhance diverse pro-apoptotic signals. Excitingly, increased anticancer activity was observed broadly in models of increasing complexity and clinical relevance (cancer cell lines, murine tumor models, canine cancer patients). Furthermore, co- administration of PAC-1 with a highly active, but toxicity-limited chemotherapeutic, was demonstrated to be both feasible and active in the treatment of a challenging canine cancer. After demonstrating that PAC-1 was capable of enhancing pro-apoptotic signaling initiated by diverse cytotoxic chemotherapeutics, the concept was explored for the treatment of brain cancers. PAC-1 penetrates the blood-brain barrier, suggesting potential for the treatment of brain cancers. Capitalizing on its ability to enhance pro-apoptotic signaling, PAC-1 was explored both as a single agent, and in combination with a DNA alkylating agent clinically used for the treatment of glioblastoma. Both strategies demonstrated antitumor activity in vivo, suggesting significant clinical utility. This work builds upon the foundation of research of PAC-1 as a single agent and suggests numerous exciting clinical pathways. Combination chemotherapy is critical for the management of many cancers, thus demonstration of increased anticancer activity in PAC-1-based combinations, and establishment of feasibility, will support its clinical development.
Issue Date:2016-07-01
Type:Thesis
URI:http://hdl.handle.net/2142/92913
Rights Information:Copyright 2016 Rachel Botham
Date Available in IDEALS:2016-11-10
Date Deposited:2016-08


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