Development of Adenoviral Ligand Libraries for Vector Targeting

PUBLIC ABSTRACT

Much of gene therapy for cancer is performed using robust gene carriers that are derived from viruses. These viral "vectors" are engineered to no longer cause their original disease, but instead deliver genes into the cancer cells. These vectors can deliver genes that directly kill the cells or genes that activate the immune system to kill the cells. Since many viruses naturally kill cells, a similar approach known as "virotherapy" uses the same viruses for cancer therapy, but in this case they are engineered to only grow and kill cancer cells and not normal cells. Based on this, gene and virotherapy show promise as new therapies to enhance or complement conventional chemotherapy, surgery, and radiation approaches. Adenovirus is one robust virus that shows promise in performing both gene therapy and virotherapy for cancer.

While gene and virotherapy have potential as treatments for breast cancer, these approaches are currently not as robust and safe as they could be because these viruses do not deliver genes specifically to breast cancer cells. Worse yet, these viruses frequently deliver genes into normal cells much more efficiently than into the cancer cells. This poor targeting means that too few genes or viruses reach too few tumor cells to effectively kill them, whereas non-specific delivery into normal cells can be the source of many of the complications and pain associated with current cancer gene or virotherapies.

To create safer gene therapy vectors for breast cancer patients, one needs to physically target these vectors to breast cancer cells and restrict therapeutic gene expression to these cells during gene therapy. To create safer virotherapy vectors for breast cancer, these viruses need to be engineered to target primary and metastatic breast cancer sites and avoid interacting with normal cells. This physical targeting will likely need to be combined with transcriptional targeting of E1A expression to generate oncolytic vectors with the highest therapeutic capacity, but with enhanced safety for breast cancer patients.

Given these issues, this project will work to address the physical targeting problem by increasing the specificity of adenoviruses for breast cancer cells. This project will engineer a system to add small proteins to adenovirus and identify those proteins that can find and bind specifically to breast cancer cells and avoid binding to normal cells. Once found, these proteins will then be tested for their ability to enhance the ability of adenovirus to deliver genes into human breast cancer cells in culture and into human breast cancer cells transplanted into mice.

If successful, this project will generate new adenoviral vectors to "home" in on breast cancer cells and avoid non-cancer cells. This work will lay the groundwork for future clinical gene therapy and virotherapy applications to treat primary and advanced metastatic breast cancer in which these "smart" targeting agents should have an enhanced ability to hunt and kill metastatic tumor cells throughout the body to more effectively control advanced breast cancer in women.