Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9578-82. doi: 10.1073/pnas.1106383108. Epub 2011 May 23.
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.
尽管新一代药物（MDV3100 和 abiraterone）在抑制去势抵抗性前列腺癌（CRPC）患者的雄激素受体（AR）信号方面取得了令人鼓舞的临床效果，但反应是可变的且短暂的。迫切需要了解耐药的基础，以优化它们的未来应用。我们推断，一种测量肿瘤内 AR 信号变化的放射性药物可以大大提高我们对 AR 通路定向治疗的理解。基于先前的观察结果，我们首先表明，前列腺特异性膜抗原（PSMA）在多种 AR 阳性前列腺癌模型中，以 AR 依赖性方式被雄激素治疗抑制。相反，抗雄激素上调 PSMA 的表达。这些表达变化，包括对雄激素拮抗剂 MDV3100 的治疗反应中 PSMA 表达的增加，可以通过使用完全人源化、放射性标记的 PSMA 抗体（64）Cu-J591 在人前列腺癌异种移植模型中通过 PET 成像进行定量测量。总的来说，这些结果表明，相对 PSMA 表达水平的变化可以使用人类准备好的成像试剂进行定量测量，并可作为 AR 信号的生物标志物，用于非侵入性评估 CRPC 患者的 AR 活性。
