Monday, May 6, 2024
5/6/2024
¿ DESCRIPTION (provided by applicant): Abstract 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.
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