Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer.
Treatment of stage IV metastatic breast cancer patients is limited to palliative options and represents an unmet clinical need. Here, we demonstrate that pharmacological inhibition of miRNA-10b - a master regulator of metastatic cell viability - leads to elimination of distant metastases in a mouse model of metastatic breast cancer. This was achieved using the miRNA-10b inhibitory nanodrug, MN-anti-miR10b, which consists of magnetic nanoparticles, conjugated to LNA-based miR-10b antagomirs. Intravenous injection of MN-anti-miR10b into mice bearing lung, bone, and brain metastases from breast cancer resulted in selective accumulation of the nanodrug in metastatic tumor cells. Weekly treatments of mice with MN-anti-miR-10b and low-dose doxorubicin resulted in complete regression of pre-existing distant metastases in 65% of the animals and a significant reduction in cancer mortality. These observations were supported by dramatic reduction in proliferation and increase in apoptosis in metastatic sites. On a molecular level, we observed a significant increase in the expression of HOXD10, which is a known target of miRNA-10b. These results represent first steps into the uncharted territory of therapy targeted to the metastatic niche.
Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Byunghee
B
Yoo
Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Amol
A
Kavishwar
Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Ping
P
Wang
Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Alana
A
Ross
Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Pamela
P
Pantazopoulos
TransCode Therapeutics, Inc., Boston, MA 02124, USA.
Michael
M
Dudley
Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Anna
A
Moore
Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Zdravka
Z
Medarova
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D061848:Optical Imaging; D023041:Xenograft Model Antitumor Assays
D035683:MicroRNAs; D004317:Doxorubicin