Project Grant R44CA257093

CLINICAL DEVELOPMENT OF FIRST-IN-CLASS THERAPY FOR METASTATIC BREAST CANCER - WE HAVE DEVELOPED A NEW THERAPEUTIC APPROACH THAT RELIES ON SPECIFIC ERADICATION OF METASTATIC TUMOR CELLS THROUGH PHARMACOLOGICAL INHIBITION OF MIRNA-10B. MIR-10B IS A MASTER REGULATOR OF THE VIABILITY OF METASTATIC TUMOR CELLS AND HAS BEEN THOROUGHLY VALIDATED AS A PROMISING THERAPEUTIC TARGET IN OVER 100 CLINICAL STUDIES ACROSS 18 METASTATIC CANCER TYPES. THE APPROACH RELIES ON A THERAPEUTIC AGENT THAT SPECIFICALLY INHIBITS MICRORNA-10B IN METASTATIC CELLS. THE THERAPEUTIC (TERMED MN-ANTI- MIR10B) CONSISTS OF ULTRASMALL DEXTRAN-COATED IRON OXIDE NANOPARTICLES (MN), CONJUGATED TO ANTAGOMIRS TARGETING MIRNA-10B. IN OUR PRECLINICAL STUDIES, WE FOUND THAT THE THERAPEUTIC IS TAKEN UP AVIDLY BY METASTATIC TUMOR CELLS IN THE LYMPH NODES, LUNGS, BONE, AND BRAIN, FOLLOWING INTRAVENOUS INJECTION. WE DEMONSTRATED THAT THE MIR-10B INHIBITORY THERAPEUTIC COULD ELICIT DURABLE REGRESSION OF LYMPH NODE AND DISTANT METASTASES IN MOUSE MODELS OF BREAST CANCER WITH NO EVIDENCE OF SYSTEMIC TOXICITY. SPECIFICALLY, JUST FOUR TO SIX WEEKLY TREATMENTS WITH MN-ANTI-MIR10B IN COMBINATION WITH LOW DOSE CHEMOTHERAPY LED TO COMPLETE REGRESSION OF DETECTABLE METASTASES. FOLLOWING ELIMINATION OF METASTASES, THERAPY WAS DISCONTINUED. NO RECURRENCE WAS OBSERVED FOR THE NATURAL LIFE OF THE ANIMALS. 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 RADIOLOGICALLY CONFIRMED METASTATIC LESIONS IN BREAST CANCER PATIENTS, AS A FINAL STEP BEFORE ENTRY INTO PHASE I CLINICAL TRIALS.