Grant: Project Grant

The nucleus is the organelle controlling the expression of gene products, with functions necessary for cellular survival. Nuclear targeting is a potential tool for improving the efficacy of chemotherapy, vaccines, and gene therapy. Research focused on understanding and harnessing nuclear targeting is a topic of intense research interest. Unfortunately, nuclear-targeting agents suffer from poor nuclear localization efficiency and, as a result, this approach has yet to become a broadly effective therapeutic standard of care for cancer. Understanding and implementing nuclear targeting strategies as well as increasing knowledge of relevant fundamental principles in nuclear transport provide paths forward for biopharmaceuticals to the nucleus, increasing their efficacy, and applications beyond cancer. Antibody-drug conjugates (ADCs) utilize antibody selectivity to deliver a conjugated cytotoxin to receptors abundantly present on tumor cells, while sparing healthy cells and, thereby, are an improvement over traditional chemotherapy. However, tumor killing can often be modest due to the inability to accumulate the cytotoxin inside tumor cells to evoke effective cytotoxicity. This is because ADCs are reliant on delivering their cytotoxin using small intracellular vesicles named endosomes. The proposed research describes our developed technology (Accum) that couples endosome escape to nuclear localization. Accum-modified ADCs are able to maintain receptor-specific tumor targeting. Once internalized into tumor cells, Accum enables ADCs to escape endosomes and efficiently localize and accumulate in the nucleus. This results in significant improvement in therapeutic efficacy. The proposed research will develop novel Accum-modified ADCs conjugated to nuclear-active cytotoxins to enhance therapeutic efficacy for breast cancer. We will also determine dominant nuclear transport pathways for breast tumor cells in order to fine-tune localization and further enhance efficacy.