Targeting Carbonic Anhydrase IX in Tumor Imaging and Theranostic Cancer Therapy

Carbonic anhydrase IX (CA-IX) is an endogenous marker for hypoxia and is regulated by the von Hippel-Lindau/hypoxia-inducible factor (VHL/HIF) oxygen-sensing pathway. CA-IX is overexpressed in many solid malignancies where aberrant vasculature and limited perfusion create low oxygen niches within the tumor microenvironment. Dysregulation of the VHL/HIF signaling pathway can lead to constitutive expression of CA-IX—a phenotype associated with clear cell renal cell carcinomas (ccRCCs). As a cell-surface metalloenzyme, CA-IX works in tandem with other proteins to regulate intracellular pH in response to hypoxia-induced metabolism. In recent years, there has been evidence implicating CA-IX in potentiating cancer invasion and metastasis. Accordingly, the inhibition of CA-IX catalytic activity represents an attractive option for the management of ccRCC and other solid tumors. In this chapter, we discuss the development of CA-IX radiopharmaceuticals and their roles in delineating tumoral CA-IX expression through imaging in preclinical and clinical settings. We will also review agents that have been repositioned as endoradiotherapeutic agents for theranostic application.