Refining Antiandrogen Therapy for Positron Emission Tomography

研究项目4(Rp4)的中心主题是提炼当前 正电子发射断层扫描(PET)在前列腺癌药效学和预测中的应用 抗雄激素治疗中的生物标志物。在ICMIC-2期间，我们对更多的 100多例去势抵抗型前列腺癌患者应用F-FDHT作为雄激素标志物 受体(AR)信号转导，F-FDG作为糖酵解的标志。我们观察到异质性在 病变，一些皮损只显示F-FDG摄取，一些皮损只摄取F-FDHT，还有一些摄取 两种追踪剂都有。我们还发现，通过SUVmax测量的F-FDG摄取与 慢性前列腺癌的预后。此外，我们还参与了临床前和早期临床 开发两种令人兴奋的新的下一代抗雄激素(阿比特龙和MDV3100)， 在帮助优化它们在临床上的使用方面，研究似乎非常有希望。在ICMIC-3期间，我们将 利用ML成像研究结果，以及从图像导向活检获得的人体组织样本 分析和动物模型，以更好地了解这些ML表型的分子基础。我们的 研究计划包括以下具体目标(SA)：SA 1：将F-FDG和F-FDHT成像联系起来 具有潜在基因改变的人类前列腺癌的表型；假设是 放射性示踪剂F-FDG和V-FDHT标记人类遗传和代谢上不同的亚群 前列腺癌。我们将使用一种新的全基因组分析策略，这是我们以前应用过的 在乳腺癌方面取得了成功。SA 2：开发AR-PET放射性配基作为药效学生物标志物 对于新的AR拮抗剂的最佳剂量；假设AR导向的放射性药物可以 在临床前模型中确定AR拮抗剂的饱和剂量，SA 3：探索V-FDG-PET 作为AR靶向治疗中的早期反应生物标志物；假设是成功地抑制 雄激素受体活性，单独或-在PTEN缺陷细胞-结合PI3K/mT0R抑制， 导致F-FDG摄取减少作为下一代治疗反应的早期标志 抗雄激素。SA 3还将确定在多个时间点进行的V-FDG-PET成像 在药物治疗过程中，可作为对新型AR拮抗剂反应和耐药性的早期标志物 人体前列腺癌的体内模型。独一无二的联合领导团队高度丰富了学习计划 在AR药理学、遗传分析和ML方面的互补技能。

The Central theme of Research Project 4 (RP4) is to refine the current use of Positron Emission Tomography (PET) in prostate cancer as pharmacodynamic and predictive biomarkers during antiandrogen therapy. During ICMIC-2, we performed molecular imaging (Ml) in more than 100 castrate resistant prostate cancer (CRPC) patients using F-FDHT as a marker of androgen receptor (AR) signaling, and F-FDG as a marker of glycolysis. We observed heterogeneity between lesions, with some lesions exhibiting only F-FDG uptake, some only F-FDHT uptake, and some uptake for both tracers. We also found that the F-FDG uptake, as measured by SUVmax, correlated inversely with prognosis in CRPC. Furthermore, we have also participated in the preclinical and early clinical development of two exciting new, next generation antiandrogens (abiraterone and MDV3100), for which Ml studies appear extremely promising in helping to optimize their use in the clinic. During ICMIC-3, we shall exploit Ml imaging study results, as well as human tissue samples obtained from image-directed biopsy analysis and animal models to better understand the molecular basis for these Ml phenotypes. Our research plan includes the following Specific Aims (SA): SA 1: To link the F-FDG and F-FDHT imaging phenotypes in human prostate cancer with underlying genetic alterations; The hypothesis is that the radiotracers F-FDG and V-FDHT mark genetically and metabolically distinct subgroups of human prostate cancer. A novel genome wide analysis strategy will be used which we have previously applied successfully in breast cancer. SA 2: To develop AR-PET Radioligands as a pharmacodynamic biomarker for optimal dosing of novel AR antagonists; the hypothesis is that AR-directed radiopharmaceuticals can determine saturating doses of AR-antagonists in a preclinical PCamodel, SA 3: To explore V-FDG-PET as an early response biomarker during AR-targeted therapies; the hypothesis is that successful inhibition of androgen receptor activity, alone or - in PTEN deficient cells - In combination with PI3K/mT0R inhibition, results in a decrease in F-FDG-uptake as an early marker of treatment response to next generation antiandrogens. SA 3 will also determine whether V-FDG-PET imaging, performed at multiple time-points during drug therapy, can serve as an early marker of response and resistance to novel AR-antagonists in in-vivo models of human prostate cancer. A unique team of co-leaders enriches the study plan with highly complementary skills, in AR pharmacology, genetic analysis and Ml.