Abstract P2-07-04: Treatment of metastatic breast cancer using two nanoparticles combined with siRNA targeting Twist1 to inhibit EMT
Authors: James B Finlay, Cai M Roberts, Gina Lowe, Ling Peng, Jeff I Zink, Fuyuhiko Tamanoi, Carlotta A Glackin
Journal: Cancer Research (2015)

Abstract Breast cancer is the 2nd leading cause of cancer related deaths among women in the US with over 240,000 diagnoses and 40,000 deaths expected in 2014. Among the more serious and deadly forms of breast cancer are the Triple Negative Breast Cancers (TNBC) (ER-, PR-, HER2-). Mortality rates among patients rise dramatically when these cancers spread beyond the primary tumor site. Therefore reduction of tumor cell dispersion is a key component to minimizing mortality rates. Epithelial-Mesenchymal Transition (EMT) is the process by which cancer cells downregulate proteins associated with cell to cell adhesion (e.g. E-cadherin) resulting in cells that are able to detach from neighboring cancer cells, invade adjacent tissue, and eventually enter the circulatory system or lymphatics. The process of EMT is tightly regulated by the transcription factor Twist1, which is often overexpressed in breast cancer. Therefore, Twist1 serves as an excellent therapeutic target whose downregulation would result in fewer metastatic cancer cells and correspondingly reduce cancer mortality. Our lab has designed and tested (in vitro) two siRNA based therapeutics that target Twist1 in a TNBC cell line (SUM 1315). These siRNA molecules have been strategically designed and modified to make them resistant to degradation, enhance silencing effects and diminish their immunogenicity. To overcome the inherent problems with delivery of siRNA (both in vitro and in vivo) we have been testing two nanoparticle delivery systems. Recent advances in nanotechnology have led to the development of a variety of nanoparticles that provide valuable tools for cancer therapy. We are testing two different types of nanoparticles in this study: The first is a Polyamidoamine (PAMAM) dendrimer (YTZ3-15) which is a truncated 3rd generation dendrimer which has been modified with a lipophilic tail to enhance cellular uptake. The second is a mesoporous silica nanoparticle (MSNs) which is able to not only deliver siRNA, but is also contains pores which allow simultaneously delivering chemotherapies such as doxorubicin. This novel siRNA gene silencing and nanotechnology-based therapy should allow us to exert more precise temporal control during breast cancer treatment. When complexed with either nanoparticle we have found significant Twist1 knock down in vitro as well as reduction of Twist1 target genes that are associated with EMT. We have also shown that Twist1 silencing reduces migration and invasion of SUM 1315 breast cancer cells in vitro Recently we began testing these siRNA+Nanoparticle complexes in an orthotopic murine model using Firefly Luciferase expressing SUM 1315 cells in immunocompromised mice (NSG). The results of this in vivo research have shown that there is significant uptake of the siRNA+Nanoparticle complexes in the tumors when compared to other organs. Results of these studies are significant because TNBC is particularly drug resistant and metastatic; and superior therapies are urgently needed to effectively treat patients with these breast cancers. This approach paves the way for TNBC treatment that incorporates Twist1 knock down (resulting in renewed chemosensitivity) and simultaneous delivery of a chemotherapy reagent. Citation Format: James B Finlay, Cai M Roberts, Gina Lowe, Ling Peng, Jeff I Zink, Fuyuhiko Tamanoi, Carlotta A Glackin. Treatment of metastatic breast cancer using two nanoparticles combined with siRNA targeting Twist1 to inhibit EMT [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-07-04.