Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2011; 108(23):9578-82. DOI: 10.1073/pnas.1106383108
Source: PubMed


Despite encouraging clinical results with next generation drugs (MDV3100 and abiraterone) that inhibit androgen receptor (AR) signaling in patients with castration-resistant prostate cancer (CRPC), responses are variable and short-lived. There is an urgent need to understand the basis of resistance to optimize their future use. We reasoned that a radiopharmaceutical that measures intratumoral changes in AR signaling could substantially improve our understanding of AR pathway directed therapies. Expanding on previous observations, we first show that prostate-specific membrane antigen (PSMA) is repressed by androgen treatment in multiple models of AR-positive prostate cancer in an AR-dependent manner. Conversely, antiandrogens up-regulate PSMA expression. These expression changes, including increased PSMA expression in response to treatment with the antiandrogen MDV3100, can be quantitatively measured in vivo in human prostate cancer xenograft models through PET imaging with a fully humanized, radiolabeled antibody to PSMA, (64)Cu-J591. Collectively, these results establish that relative changes in PSMA expression levels can be quantitatively measured using a human-ready imaging reagent and could serve as a biomarker of AR signaling to noninvasively evaluate AR activity in patients with CRPC.

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Available from: Neil H Bander,
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    • "Three human prostate cancer cell lines with different levels of PSMA expression were used to evaluate localization and internalization of probes: PC3 M-LN4 (negative), 22Rv1 (low), and LNCaP (high) [32, 33]. PC3 M-LN4 and 22Rv1 cells were incubated at 37°C for 1 h with 300 nM YC-27 800CW or 1 μg PSMA 800CW. "
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    ABSTRACT: Prostate cancer is the most frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR) technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds. In vivo targeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy. In vitro and in vivo blocking studies confirmed YC-27 specificity. In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections.
    04/2014; 2014(7):104248. DOI:10.1155/2014/104248
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    • "This statement may be confirmed by reports indicating that changes in PSMA expression can also serve as a noninvasive marker for imaging AR signaling and monitoring response to conventional treatments [29, 32]. Additionally, the molecular imaging strategy using tracers directed towards PSMA could also have a more significant clinical impact considering that PSMA is upregulated in response to antiandrogen therapy [33]. This may have important therapeutic implications since a toxin-conjugated PSMA-targeted mAb could be an effective combination therapy with antiandrogens. "
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    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
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    • "Similarly, androgen receptors expressed in primary or metastatic prostate cancers have been imaged with 18F-fluorodihydrotestosterone, which binds to their ligand-binding domain [75]. More recently, a fully humanized, radiolabeled antibody against prostate-specific membrane antigen was developed to image intracellular androgen receptor signaling [76, 77]. "
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    ABSTRACT: The discovery of the Warburg effect in the early twentieth century followed by the development of the fluorinated glucose analogue 18F-fluorodeoxyglucose (18F-FDG) and the invention of positron emission tomographs laid the foundation of clinical PET/CT. This review discusses the challenges and obstacles in clinical adoption of this technique. We then discuss advances in instrumentation, including the critically important introduction of PET/CT and current PET/CT protocols. Moreover, we provide evidence for the clinical utility of PET/CT for patient management and its potential impact on patient outcome, and address its cost and cost-effectiveness. Although this review largely focuses on 18F-FDG imaging, we also discuss a variety of additional molecular imaging approaches that can be used for cancer phenotyping with PET. Throughout this review we emphasize the critical contributions of CT to the strength of PET/CT.
    09/2013; 1(3). DOI:10.1007/s40134-013-0016-x
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