A major limitation of current strategies targeting growth factors in cancer is achieving a high local concentration of therapeutics to keep growth factors at very low levels for extended periods of time. In vivo production of monoclonal antibody (mAb)-based therapeutics in tumor cells provides an attractive alternative to treatment with repeated high bolus injections, as expression of the secreted therapeutic in tumor cells could provide high local concentrations that could act in a paracrine fashion to quench growth factors in the tumor microenvironment with minimal side effects. In contrast to tumorlytic viral approaches, this strategy does not require that all tumor cells be infected, as uninfected cells are still subject to bystander effects of the secreted therapeutic. My project focuses on the use of an adenoviral delivery system to transduce tumor cells with genes encoding secreted payloads for the paracrine delivery of protein-based therapeutics to the tumor microenvironment. These payloads consist of growth factor neutralizing agents that target a series of growth factors overexpressed in cancer (i.e. IL-6, HGF, IGF-1, and EGFR-family associated ligands). My project accomplishes this objective through two specific aims.
Aim 1 : To develop an adenoviral delivery system for tumor production of payloads in HER-2 expressing tumor lines. Using an adaptor system that utilizes a specific target module for the delivery of an adenovirus to HER2-overexpressing tumors, I will test a series of growth factor neutralizing agents for delivery and secretion efficiency in HER2 tumor cell lines.
Aim 2 : To evaluate efficacy and safety of adenoviral treatment in HER2-expressing tumors in a murine model. Using SCID mice harboring HER2-positive tumors, the delivery system described will be use to transduce tumor cells with genes encoding these therapeutic agents.

Public Health Relevance

This section has been rewritten entirely from the original submission (Dec 8, 2013). One mechanism that allows cancer cells to survive and proliferate is through the secretion of growth factors. Growth factors are proteins or hormones that serve as signaling molecules that tell neighboring tumor cells to grow and divide. One strategy to treat cancer is to capture or neutralize these tumor-secreted growth factors through binding to protein-based drugs, or therapeutics. The goal of my project is to develop a strategy of selectively infecting tumor cells with a virus that causes the tumor itself to synthesize and secrete growth factor-neutralizing drugs to block the effects of the growth factors they secrete. This strategy allows for a high concentration of the drug to be localized to the tumor eliminating the need to perform multiple, high-dose injections into a patient's bloodstream which could cause adverse side effects.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Mcguirl, Michele
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University of Zurich
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