John L. Joyal Imaging Tumor Hypoxia with Radiohalogenated Inhibitors of Carbonic Anhydrase IX Project Summary The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose and characterize disease by probing the phenotypic identity and biochemical composition of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins allow the use of noninvasive imaging techniques, such as molecular imaging or nuclear medicine, for detecting the presence and quantity of tumor associated proteins, thereby providing vital information related to the diagnosis and extent of disease, prognosis and therapeutic management options. Hypoxia is a hallmark of most solid tumors which has a direct impact on the success of radiotherapy and some chemotherapy through the reduction in tissue oxygen. It plays a vital role in triggering changes in gene expression which subsequently influence protein expression, enzymatic activities, metabolism and possibly the metastatic potential of cancer. The goal of this proposal is to develop a series of novel iodine-labeled molecular imaging pharmaceuticals that target hypoxia by binding to the hypoxia-induced cell surface protein, carbonic anhydrase IX (CA-IX) for imaging by single photon emission tomography (SPECT). The research plan combines high affinity targeting molecules to deliver a diagnostic or therapeutic radionuclide. Several classes of selective and cell membrane impermeable CA-IX inhibitors have been described in the primary literature representing a foundation for the design of radiotracers. Analogs of CA-IX inhibitors will be synthesized first as non-radiolabeled iodine-containing molecules and tested to verify binding to CA-IX in biochemical and cellular assays. Compounds demonstrating high affinity binding to CA-IX will then be radiolabeled with 123I and examined for cell binding, and hypoxia-dependent tumor uptake and retention in mice bearing human cancer xenografts. As CA-IX is a cell surface protein, the target will be readily accessible, with a straightforward pharmacokinetic analysis. The strategy takes advantage of the tight regulation of hypoxia-induced transcription of CA-IX;it is unlike the mechanism of currently available hypoxia sensors which monitor oxygen content or copper reduction potential. In addition, it will complement tumor imaging by 18FDG which cannot discriminate normoxia from hypoxia. With the proposed radiopharmaceutical, individualized patient management will be realized, whereby tumors can be assessed for hypoxia before choosing an appropriate therapy thus improving treatment selection and patient outcome. This work will expand upon our previous success in the design, synthesis and development of radiopharmaceuticals such as 2-methyl-p-[123I]-iodophenylpentadecanoic acid (BMIPP) for imaging cardiac ischemia and 123I-labeled inhibitors of prostate specific membrane antigen for the detection of prostate cancer. We believe that the 123I- labeled CA-IX radiotracers could be exploited for the diagnosis, staging, and prognosis of solid tumors.
John L. Joyal Imaging Tumor Hypoxia with Radiohalogenated Inhibitors of Carbonic Anhydrase IX Project Narrative Hypoxia is a hallmark of most solid tumors and has been shown to be related to poor prognosis. The goal of this proposal is to develop a series of novel hypoxia imaging radiopharmaceuticals that would allow the characterization of a patient's cancer by targeting a key hypoxia-regulated enzyme, carbonic anhydrase IX. The ability to detect tumor hypoxia would allow clinicians to alter the intensity of radiotherapy or seek chemotherapies that are less influenced by tumor oxygen content and potentially lead to improved outcomes.
