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    Awarded Grants
    Her2-Targeted Adenovirus Vectors for Imaging and Gene Therapy of Breast Cancer

    Scientific Abstract:
    Background: Poor outcomes of adenovirus (Ad)-based gene therapy for breast cancer are due to suboptimal gene delivery by Ad vectors. This is because Ad infection critically depends on the presence of the CAR receptor on the surface of the target cells; this receptor is poorly expressed by breast tumors. At the same time, high expression of this receptor by most normal tissues results in sequestration of the Ad vector by normal tissues, reduction of its therapeutic effect, increased cytotoxicity, and anti-Ad immune responses in patients. Thus, gene therapy for breast cancer will benefit from the development of tumor-selective vectors. Objective/Hypothesis: Our objective is to develop a novel gene-therapy-based approach to eradicating tumors by designing Ad vectors capable of selective infection and destruction of tumor cells that express Her2, a major molecular marker of breast carcinomas. Our hypothesis is that by tailoring Ad tropism, we can achieve more efficient transduction of tumors and more stringent control over Ad vector dissemination in vivo and, thus, target the therapy to the site of the disease. Specific Aims: (i) To design the genetic fusions of the Ad fiber with the Her2-specific ligands. (ii) To derive tropism-modified Ad vectors and evaluate their target specificity. (iii) To demonstrate improved tumor specificity of Her2-targeted Ad vectors in a murine model of breast cancer. Study Design: Novel ankyrin-derived ligands, which are specific to the extracellular domain of Her2, will be genetically fused with the Ad fiber protein. The resultant fusions will be characterized and incorporated into Ad virions. These Ad vectors will be used for killing of tumor cells in vitro and eradication of breast tumor xenografts established in nude mice. Potential Outcomes and Benefits of the Research: This work will result in the derivation of a new generation of tropism-modified Ad vectors with superior selectivity for Her2-positive tumors, improved safety profiles, and simplified manufacturing characteristics. Thus, it will address key issues that limit the utility of the present-generation Ad vectors and their clinical use in patients with breast cancer. The development of this novel vector system will be a major technological advance in gene therapy for this disease.

    Lay Abstract:
    Background: After more than a decade of effort, the success of gene therapy for breast cancer has been only marginal. This is largely because of the low efficiency of the gene transfer vehicles, or vectors, used to deliver genes to tumors. None of the presently available vectors are able to deliver the gene payload to tumors in a selective manner. Thus, these vectors function as loose canons, randomly infecting both tumors and normal tissues. This results in low efficiency of the therapy and a number of very serious side effects. Objective/Hypothesis: It is our objective to design a novel vector for gene therapy for breast cancer by genetically modifying the tissue specificity of human adenovirus (Ad). Our hypothesis is that by directing the vector to Her2, a characteristic marker of breast carcinomas, we will make it tumor specific. This new Ad vector will selectively infect and destroy breast tumor cells, which express Her2, but will not infect the cells of normal tissues. Thus, it will be much safer for patients. Specific Aims: (i) To design the genetic fusions of the Ad fiber with the Her2-specific ligands. (ii) To derive tropism-modified Ad vectors and evaluate their target specificity. (iii) To demonstrate improved tumor specificity of Her2-targeted Ad vectors in a murine model of breast cancer. Study Design: We will modify the structural component of the Ad particle–the fiber–to incorporate a Her2-targeting molecule. We will manufacture and purify each modified fiber and confirm their ability to interact with Her2. Next, we will design recombinant Ad particles containing such Her2-targeting fibers and employ them to destroy experimental breast tumors in mice. Potential Outcomes and Benefits of the Research: The success of this work will result in a new generation of gene delivery vectors with superior selectivity for Her2-positive tumors and improved safety. By improving upon these key characteristics of Ad gene therapeutics, we will shorten their journey from the laboratory bench to the clinic. Importantly, the proposed configuration of the Ad vector will be fully compatible with all other Ad-based gene therapy interventions proposed to date for breast cancer.