Imaging Androgen Receptor Signaling with a Radiotracer Targeting Free Prostate-Specific Antigen

Department of Surgery, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cancer Discovery (Impact Factor: 19.45). 04/2012; 2(4):320-7. DOI: 10.1158/2159-8290.CD-11-0316
Source: PubMed


Despite intense efforts to develop radiotracers to detect cancers or monitor treatment response, few are widely used as a result of challenges with demonstrating clear clinical use. We reasoned that a radiotracer targeting a validated clinical biomarker could more clearly assess the advantages of imaging cancer. The virtues and shortcomings of measuring secreted prostate-specific antigen (PSA), an androgen receptor (AR) target gene, in patients with prostate cancer are well documented, making it a logical candidate for assessing whether a radiotracer can reveal new (and useful) information beyond that conferred by serum PSA. Therefore, we developed (89)Zr-labeled 5A10, a novel radiotracer that targets "free" PSA. (89)Zr-5A10 localizes in an AR-dependent manner in vivo to models of castration-resistant prostate cancer, a disease state in which serum PSA may not reflect clinical outcomes. Finally, we demonstrate that (89)Zr-5A10 can detect osseous prostate cancer lesions, a context where bone scans fail to discriminate malignant and nonmalignant signals. SIGNIFICANCE: This report establishes that AR-dependent changes in PSA expression levels can be quantitatively measured at tumor lesions using a radiotracer that can be rapidly translated for human application and advances a new paradigm for radiotracer development that may more clearly highlight the unique virtues of an imaging biomarker.

Download full-text


Available from: Jason P Holland,
  • Source
    • "Of great interest is the fact that 89Zr-5A10 is suitable for the quantification of AR transcriptional activity in preclinical models of androgen independent models. Additionally, 89Zr-5A10 is colocalized in PSA- and AR-positive Pca models and quantitatively predicted response to antiandrogen therapy [25]. This radiotracer appears to preferentially target malignant tumor cells and therefore may become a more predictive imaging biomarker in prostate cancer [26]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (Pca) is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.
    BioMed Research International 10/2013; 2013:460546. DOI:10.1155/2013/460546 · 2.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Serum prostate-specific antigen (PSA) levels are used to monitor the development of prostate cancer, recurrence after surgery, and response to subsequent therapy. However, the clinical implications often are difficult to interpret. Ulmert and colleagues report use of a positron-emitting labeled monoclonal antibody directed to a unique PSA epitope to noninvasively image PSA-positive prostate cancer xenografts and to measure both androgen-stimulated PSA expression and androgen therapy-responsive PSA decreases.
    Cancer Discovery 04/2012; 2(4):301-3. DOI:10.1158/2159-8290.CD-12-0067 · 19.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this era of systems biology, the tide of information derived from "omic" technologies (genomics, proteomics, etc.) has sparked a revolution in drug design, with many industrial and academic programs now embracing the concepts of molecular medicine (i.e., targeting changes in specific proteins or pathways) as measures of treatment efficacy and outcome. This approach has yielded a plethora of new preclinical therapeutics directed at novel targets within oncology. In many ways, the evolution of molecular imaging agents as diagnostic probes mirrors that of chemotherapeutics; yet despite an increasing number of PET and SPECT radiotracers being evaluated in human trials, relatively few agents have found widespread use in clinical oncology. In light of this observation, is it time to reevaluate our strategies for radiopharmaceutical design and use? In this article, we argue that PET has enormous potential to deliver clinically relevant information on disease dynamics that extends beyond mapping the density and spatial distribution of a target. Recent developments in targeting pharmacodynamic biomarkers aim to exploit better the advantages of functional PET by detecting changes in signal transduction pathways, particularly in response to disease progression or treatment in cancer.
    Journal of Nuclear Medicine 08/2012; 53(9):1333-6. DOI:10.2967/jnumed.112.105387 · 6.16 Impact Factor
Show more