Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

SIMPLE SUMMARY: Tumor hypoxia remains a significant problem in the effective treatment of most cancers. Tumor cells within hypoxic niches tend to be largely resistant to most therapeutic modalities, and adaptation of the cells within the hypoxic microenvironment imparts the cells with aggressive, invasive behavior. Thus, a major goal of successful cancer therapy should be the eradication of hypoxic tumor cells. Carbonic Anhydrase IX (CAIX) is an exquisitely hypoxia induced protein, selectively expressed on hypoxic tumor cells, and thus has garnered significant attention as a therapeutic target. In this Commentary, we discuss the current status of targeting CAIX, and future strategies for effective, durable cancer treatment. ABSTRACT: Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- and extracellular pH and acidosis. Significant advances have been made recently in the development of therapeutic targeting of CAIX. These approaches include antibody-based immunotherapy, as well as use of antibodies to deliver toxic and radioactive payloads. In addition, a large number of small molecule inhibitors which inhibit the enzymatic activity of CAIX have been described. In this commentary, we highlight the current status of strategies targeting CAIX in both the pre-clinical and clinical space, and discuss future perspectives that leverage inhibition of CAIX in combination with additional targeted therapies to enable effective, durable approaches for cancer therapy.