Treatment options for patients with metastatic breast cancer are severely limited and ultimately rely on palliative care representing an unmet clinical need. Previous studies have demonstrated that microRNAs play a significant role in the formation of metastasis including those from breast cancer. Considering the paucity of options for patients with metastasis from breast cancer, in this proposal we focused on targeting miR-10b proven to be responsible for metastatic spread. While previous studies showed that miR-10b drives invasion and migration of cancer cells from primary tumors, our recent discovery demonstrated that in metastatic cells it is also responsible for cell viability and proliferation and that survival of metastatic cells crucially depends on the high level of miR-10b expression. This discovery formed a cornerstone of our therapeutic strategy aimed at specific eradication of metastatic tumor cells. This will be done using imaging-capable modular nanodrugs, which distribute to lung, liver, bone, or brain metastases. These nanodrugs consist of magnetic nanoparticles that carry locked-nucleic acid (LNA) oligonucleotides inhibiting microRNA-10b. Targeting moieties conjugated to the nanoparticles facilitate their accumulation at distant metastatic sites. Previously we have demonstrated the feasibility of the proposed approach. Delivery of the nanodrug to lymph nodes with already formed metastases resulted in arrest of metastatic progression by inhibiting tumor cell proliferation and causing apoptosis, which is a phenomenon that has not been described before. When treatment with the nanodrug was combined with a low-dose of conventional chemotherapy (doxorubicin), there was regression and permanent elimination of lymph node or lung metastases without relapse even after treatment was discontinued. Unlike conventional chemotherapies, this therapeutic protocol was not associated with animal morbidity/mortality. In the current application we propose to use the miR10b-inhibitory nanodrug in combination with low-dose chemotherapy (where necessary) for targeting breast cancer metastases in distant organs. Noninvasive imaging will be used to evaluate the delivery of the nanodrug. If successful, this approach could be a life- extending (and possibly, life saving) alternative for patients with advanced metastatic disease for whom salvage therapy is the only current option.
In the proposed research, we will employ nanodrugs capable of inhibiting the pro- metastatic miRNA-10b in vivo with the goal of regressing breast cancer metastatic to brain, lungs, bone, and liver and effecting a permanent cure. What is unique about the study is the potential to mediate a robust therapeutic effect through molecular reprogramming of the metastatic cancer cell.
