Nanoparticles-mediated combination therapy for breast cancer

Abstract Despite recent advances in treatment, metastatic breast cancer (mBCa) remains one of the leading causes of cancer-related deaths in the United States among women. Chemotherapy remains fundamental to the management of all molecular subtypes of mBCa and anthracyclines and taxanes are two major types of chemotherapeutics. One major issue in chemotherapy is drug resistance, both intrinsic and acquired. In addition, the overall benefit of immunotherapy remains limited for mBCa. There is still a need to develop novel strategies to overcome chemoresistance and/or the poor response of immunotherapy in mBCa. IRhom proteins (iRhom 1 and iRhom 2) are catalytically inactive relatives of rhomboid intramembrane proteases and play an important role in regulating the stability and trafficking of other membrane proteins. IRhom1 is overexpressed in several types of cancers including breast cancer (BCa) and knockdown of iRhom1 led to significant inhibition of tumor growth in vivo. We have shown that knockdown of iRhom1 led to sensitization of tumor cells to several chemotherapeutic agents including doxorubicin (DOX) and SAHA. We have further shown that iRhom1 plays a role in modulating tumor immune response and knockout of iRhom1 resulted in an improvement in tumor immune microenvironment. To facilitate the therapeutic translation of these novel findings, we have developed a new nanocarrier that is highly effective in selective codelivery of iRhom1 siRNA and chemotherapeutic agents to tumors. We have also developed a bioengineered iRhom1 pre-siRNA (pre-siiRhom1) that is biotransformed to mature siRNA upon intracellular delivery. We have further developed DOX-SAHA, a prodrug conjugate to facilitate codelivery of the two drugs of synergistic action. This application is focused on further improvement of the safety and the tumor-targeting efficiency of the nanocarrier as well as the overall therapeutic efficacy of codelivery of DOX-SAHA/pre-siiRhom1. The underlying mechanism will also be investigated. Three specific aims will be pursued in this proposal. Aim 1 will develop and characterize an improved nanocarrier for co-formulating DOX-SAHA and pre-siiRhom1. Aim 2 will investigate the tumor-targeting efficiency of the nanocarrier, and the PK and tissue biodistribution of DOX-SAHA and pre-siiRhom1 co-formulated in the nanocarrier. Aim 3 will investigate the in vivo therapeutic efficacy, the underlying mechanism, and the toxicity profile of the combination therapy in murine and human BCa models. Successful completion of this study will lead to the development of a new combination therapy for the treatment of different types of cancers including mBCa.