Article

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: 15.93). 04/2012; 2(4):320-7. DOI: 10.1158/2159-8290.CD-11-0316
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
107 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Prostate cancer is a leading cause of death in the male population of the western world. Human kallikrein-related peptidase 2 (hK2) is abundantly expressed in malignant prostatic tissue, and its gene, KLK2, is regulated by the androgen receptor. 11B6 is a murine IgG1 monoclonal antibody directed against free human hK2. In this study, we performed a preclinical evaluation of 111In-labelled 11B6 in mouse xenografts to investigate its potential in the clinical staging and assessment of metastatic prostate cancer. Methods 11B6 was radiolabelled with 111In through CHX-A″-DTPA chelation. In vivo biodistribution and uptake of 111In-DTPA-11B6 were measured until 168 h post-injection in NMRI nude mice bearing subcutaneous LNCaP xenografts. The binding specificity to hK2 was evaluated by both in vivo competitive binding assays with excess non-labelled 11B6 and hK2-negative DU145 xenografts. SPECT/CT imaging of subcutaneous and intra-tibial LNCaP xenografts was used to visualize the tumours. Results Tumour uptake of 111In-DTPA-11B6 in LNCaP xenografts was 19% ± 0.78%IA/g at 48 h, giving a tumour-to-blood ratio of 1.6, which increases to 2.4 at 1 week post-injection. Accumulation was low in other organs except for the salivary glands, which is probably the result of cross-reactivity with mouse kallikreins. Significantly lower tumour accumulation was observed in competitive assays and DU145 xenografts. SPECT/CT imaging could clearly visualize the subcutaneous and intra-tibial LNCaP xenografts. Conclusions Our study demonstrates the potential of 111In-DTPA-11B6 for the detection of metastatic prostate cancer and monitoring anti-androgen therapy, as it exhibits an increased uptake and accumulation in viable tumour when compared to normal tissue. A humanised version of the 11B6 monoclonal antibody is currently under evaluation.
    10/2014; 4(51). DOI:10.1186/s13550-014-0051-5
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite advances in the treatment of castration-resistant and bone metastatic prostate cancer (PCa), there is still no clear demonstration that PCa growth and metastases can be unambiguously detected. We review recent advances including our own development of near-infrared fluorescence (NIRF) and near-infrared nuclear (NIRN) imaging approaches. We validated our results in experimental models of PCa bone and soft tissue metastases including PCa colonization at metastatic sites by injecting PCa cells either intratibially or intracardiacally. We describe our experience using noninvasive imaging and targeting modalities to probe PCa tumors grown at metastatic sites, molecular studies to understand the multiple molecular and cellular processes within tumor cells and their interactions with the tumor microenvironment, and targeting tumor growth at metastatic bone site. In this review, current knowledge and emerging technologies based on NIRF and NIRN disciplines will be summarized. Additionally the mechanisms of differential uptake of these agents by normal and cancerous cells will be described.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for (89)Zr(4+); however, accumulation of (89)Zr in the bones of mice suggests that (89)Zr(4+) is released from DFO in vivo. An improved chelator for (89)Zr(4+) could eliminate the release of osteophilic (89)Zr(4+) and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator - 3,4,3-(LI-1,2-HOPO) or HOPO - as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex which was evaluated experimentally and theoretically. The stability of (89)Zr-HOPO matched or surpassed that of (89)Zr-DFO in every experiment. In healthy mice, (89)Zr-HOPO cleared the body rapidly with no signs of demetallation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for (89)Zr-based PET imaging agents.
    Journal of Medicinal Chemistry 05/2014; 57(11). DOI:10.1021/jm500389b · 5.48 Impact Factor

Full-text

Download
44 Downloads
Available from
Jun 3, 2014