Crosslinking-based targeted therapy for triple-negative breast cancer
NIH
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
Abstract  The HER1 and/or HER3 receptors are overexpressed in most triple-negative breast cancers (TNBCs), a subtype of breast cancer that lacks estrogen receptor, progesterone, and HER2 expression and is associated with poor prognosis and a high lung and brain metastasis rate. Chemotherapy is the mainstay of TNBC treatment. Our long-term goal is to develop more effective therapy for this aggressive subtype of breast cancer. In this proposal, we aim to develop a novel crosslinking-based targeted therapy. For this purpose, we will create a series of multi-functional DNA-affibody-drug nanoparticles containing multiple copies of HER1 and/or HER3 specific affibody molecules covalently coupled to a DNA nanostructure, of which the latter binds to tens of small molecule drugs such as THZ1. In the presence of these nanoparticles, HER1+ and/or HER3+ TNBC cells will be tightly bound together, thus preventing metastasis in its initial stage. In the cross-linked TNBC cell clusters, the small molecule anticancer agent THZ1 reversibly bound to the nanoparticles will be released slowly, resulting in killing of crosslinked TNBC cells. These nanoparticles can bind to HER1+ and/or HER3+ TNBC cells in primary tumors, metastatic sites, and circulation. In our preliminary study, cultured HER1+ TNBC cells were crosslinked together to form cell clusters with a 96% crosslinking efficiency, 99% migration inhibition, and 90% invasion inhibition by a DNA-4ZHER1-THZ1 nanoparticle (drug-to-cargo ratio is 50).  To enhance the efficiency and overcome the resistance to HER1 inhibitors, a novel DNA-2ZHER1-2ZHER3-THZ1 nanoparticle that targets dual HER1 and HER3 will be synthesized and tested in this study. Our design and hypothesis will be tested with the following specific aims: In specific aim 1, we will prepare a DNA-2ZHER1-2ZHER3- drug nanoparticle for targeting HER1- and/or HER3-overexpressing TNBC. In specific aim 2, we will evaluate the inhibition of HER1- and HER3-overexpressing TNBC cell growth and metastasis by the DNA-2ZHER1-2ZHER3- drug nanoparticle in vitro. In specific aim 3, we will study distribution and pharmacokinetics of selected DNA- 2ZHER1-2ZHER3-drug nanoparticle in healthy mice, and to evaluate its suppression of mammary tumor growth and metastasis in TNBC xenograft models.  If successful, this innovative approach will open a new avenue for developing new therapy for treatment of TNBC. The pilot study will lay a foundation for further studies to investigate the utilities and mechanisms of the new class of anticancer agents for targeted therapy. Project Narrative In this proposal, our long-term goal is to develop a novel “crosslinking-based targeted therapy” for treatment of triple-negative breast cancer patients. If successful, this innovative therapy for the prevention and treatment of TNBC metastasis should have a significant impact on reducing the mortality rate in triple-negative breast cancer patients.
Non-SBIR/STTR