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MODELING ANTI-TUMORAL EFFECTS OF DRUG-INDUCED
ACTIVATION OF THE CELL-EXTRINSIC APOPTOTIC PATHWAY
by
Brittany Kay
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Ful llment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOMEDICAL ENGINEERING)
August 2012
Copyright 2012 Brittany Kay
Object Description
| Title | Modeling anti-tumoral effects of drug-induced activation of the cell-extrinsic apoptotic pathway |
| Author | Kay, Brittany P. |
| Author email | bkay@usc.edu;brittany.p.kay@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biomedical Engineering |
| School | Viterbi School of Engineering |
| Date defended/completed | 2012-06-06 |
| Date submitted | 2012-07-14 |
| Date approved | 2012-07-15 |
| Restricted until | 2012-07-15 |
| Date published | 2012-07-15 |
| Advisor (committee chair) | D'Argenio, David Z. |
| Advisor (committee member) |
Khoo, Michael C.K. MacKay, J. Andrew |
| Abstract | RshApo2L/TRAIL and Conatumumab bind to transmembrane death receptors and trigger the extrinsic cellular apoptotic pathway through a caspase-signaling cascade resulting in cell death. Tumor size time series data from rodent tumor xenograft (COLO205) studies following administration of either of these two pro-apoptotic receptor agonists (PARAs) were combined to develop an intracellular-signaling tumor-regression model that includes two levels of signaling: upstream signals unique to each compound (representing initiator caspases), and a common downstream apoptosis signal (representing executioner caspases) shared by the two agents. Pharmacokinetic (PK) models for each drug were developed based on plasma concentration data following intravenous (IV) and/or intraperitoneal (IP) administration of the compounds and were used in the subsequent intracellular-signaling tumor-regression modeling. A model relating the PK of the two PARAs to their respective and common downstream signals, and to the resulting tumor burden was developed using mouse xenograft tumor size measurements from 448 experiments that included a wide range of dose sizes and dosing schedules. ❧ Deficiencies in the original model's ability to describe data from some of the experimental groups led to exploration of several hypotheses for a reduction of drug effect. Both empirical and semi-mechanistic reduction-of-drug-effect models were investigated. All three modified models showed marked improvement of fit, especially for data from the long-term dosing experiments; the greatest improvement (by model-comparison metrics) came from incorporation of a pro-survival signal -- consistent with the hypothesis that PARAs may also cause the upregulation of pro-survival factors that can lead to a reduction in their effectiveness with treatment. ❧ Combination therapy data, for which a PARA was co-dosed with a cytotoxic agent, was analyzed using an interaction model. The model was generally able to describe the data; however, the type of data available could only minimally inform the interaction model because of the substantial effects of the chosen monotherapy regimens. |
| Keyword | apoptosis; PKPD; PARA; extrinsic apoptotic pathway; cancer; modeling; caspase |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Kay, Brittany P. |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-KayBrittan-954.pdf |
Description
| Title | Page 1 |
| Full text | MODELING ANTI-TUMORAL EFFECTS OF DRUG-INDUCED ACTIVATION OF THE CELL-EXTRINSIC APOPTOTIC PATHWAY by Brittany Kay A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Ful llment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOMEDICAL ENGINEERING) August 2012 Copyright 2012 Brittany Kay |
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