We have developed a new therapeutic approach that relies on specific eradication of metastatictumor cells through pharmacological inhibition of miRNA-10b. miR-10b is a master regulator of theviability of metastatic tumor cells and has been thoroughly validated as a promising therapeutic targetin over 100 clinical studies across 18 metastatic cancer types. The approach relies on a therapeuticagent that specifically inhibits microRNA-10b in metastatic cells. The therapeutic (termed MN-anti-miR10b) consists of ultrasmall dextran-coated iron oxide nanoparticles (MN), conjugated toantagomirs targeting miRNA-10b. In our preclinical studies, we found that the therapeutic is taken upavidly by metastatic tumor cells in the lymph nodes, lungs, bone, and brain, following intravenousinjection. We demonstrated that the miR-10b inhibitory therapeutic could elicit durable regression oflymph node and distant metastases in mouse models of breast cancer with no evidence of systemictoxicity. Specifically, just four to six weekly treatments with MN-anti-miR10b in combination with lowdose chemotherapy led to complete regression of detectable metastases. Following elimination ofmetastases, therapy was discontinued. No recurrence was observed for the natural life of theanimals. In this application, we propose to perform key translational experiments including IND-enabling and IND-supported imaging studies that would assess the uptake of MN-anti-miR10b byradiologically confirmed metastatic lesions in breast cancer patients, as a final step before entry intophase I clinical trials.
Public Health Relevance Statement: We have developed a new therapeutic approach that relies on specific
eradication of metastatic tumor cells through pharmacological inhibition of
miRNA-10b. In this application, we propose to perform key translational
experiments including IND-enabling and IND-supported imaging studies that
would assess the uptake of MN-anti-miR10b by metastatic lesions in breast
cancer patients.
Project Terms: Micro RNA ; miRNA ; miRNAs ; MicroRNAs ; Distant Cancer ; Distant Metastasis ; Tissue Sample ; Dose ; Breast tumor model ; mammary cancer model ; mammary tumor model ; Breast Cancer Model ; Detection ; Quantitative RTPCR ; qRTPCR ; Quantitative Reverse Transcriptase PCR ; Reproducibility ; Cancer Patient ; preclinical study ; pre-clinical study ; cost ; nanotherapeutic ; nano therapeutic ; cancer type ; chemotherapy ; mouse model ; murine model ; therapeutic target ; therapeutic development ; therapeutic agent development ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; phase 2 study ; phase II study ; Institutional Review Boards ; IRB ; IRBs ; clinical risk ; Breast Cancer Patient ; Breast Tumor Patient ; Metastatic breast cancer ; systemic toxicity ; experimental study ; experiment ; experimental research ; clinical development ; imaging study ; iron oxide nanoparticle ; iron oxide nano particle ; pharmacokinetics and pharmacodynamics ; PK/PD ; Prognosis ; Animals ; Behavior ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biopsy ; Blood ; Blood Reticuloendothelial System ; bone ; Brain ; Brain Nervous System ; Encephalon ; malignant breast neoplasm ; Breast Cancer ; malignant breast tumor ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cells ; Cell Body ; Clinical Research ; Clinical Study ; Clinical Trials ; Dextrans ; dextran ; Disease ; Disorder ; Investigational Drugs ; Investigational New Drugs ; Human ; Modern Man ; intravenous injection ; Lung ; Lung Respiratory System ; pulmonary ; lymph nodes ; Lymph Node Reticuloendothelial System ; Lymph node proper ; Lymphatic nodes ; lymph gland ; lymphnodes ; Magnetic Resonance Imaging ; MR Imaging ; MR Tomography ; MRI ; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance ; NMR Imaging ; NMR Tomography ; Nuclear Magnetic Resonance Imaging ; Zeugmatography ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; Neoplasm Metastasis ; Metastasis ; Metastasize ; Metastatic Lesion ; Metastatic Mass ; Metastatic Neoplasm ; Metastatic Tumor ; Secondary Neoplasm ; Secondary Tumor ; cancer metastasis ; tumor cell metastasis ; Pathology ; Patients ; Drug Kinetics ; Pharmacokinetics ; Pharmacology ; Positron-Emission Tomography ; PET ; PET Scan ; PET imaging ; PETSCAN ; PETT ; Positron Emission Tomography Medical Imaging ; Positron Emission Tomography Scan ; Rad.-PET ; positron emission tomographic (PET) imaging ; positron emission tomographic imaging ; positron emitting tomography ; Radiology Specialty ; General Radiology ; Radiology ; Radiation therapy ; Radiotherapeutics ; Radiotherapy ; radiation treatment ; radio-therapy ; treatment with radiation ; Recurrence ; Recurrent ; RNA ; Non-Polyadenylated RNA ; RNA Gene Products ; Ribonucleic Acid ; Rodent ; Rodentia ; Rodents Mammals ; Specificity ; Tissues ; Body Tissues ; Toxicology ; Work ; Measures ; Drug Delivery Systems ; Drug Delivery ; Investigational New Drug Application ; base ; Organ ; Blood specimen ; Blood Sample ; sensor ; Site ; Clinical ; Phase ; Serum ; Blood Serum ; uptake ; Therapeutic ; Therapeutic Agents ; Metastatic Cancer ; Metastatic Malignant Neoplasm ; Disseminated Malignant Neoplasm ; Research Specimen ; Specimen ; Life ; Protocol ; Protocols documentation ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; Tumor Cell ; neoplastic cell ; Biopsy Sample ; Biopsy Specimen ; Primary Tumor ; Primary Neoplasm ; intervention therapy ; Therapeutic Intervention ; Sampling ; drug development ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ;
