Abstract: The present invention relates to a therapeutic comprising an osteopontin isoform a (“OPNa”) inhibitor where the OPNa inhibitor blocks activity of extracellular OPNa exon 4. The OPNa inhibitor is selected from the group consisting of (i) an exon-4 specific antibody or binding portion thereof; (ii) a peptide mimic of OPNa exon 4 or a fragment thereof; (iii) a nucleic acid aptamer that specifically binds to OPNa exon 4 or a fragment thereof; and (iv) a peptide inhibitor that binds to OPNa exon 4 or a fragment thereof. The present invention also relates to methods of inhibiting tumor growth and/or metastasis in a subject, treating a subject with chemotherapeutic resistance, and methods of increasing tumor cell sensitivity to a cancer therapeutic by administering an OPNa inhibitor according to the present invention.