Refining Antiandrogen Therapy for Positron Emission Tomography

改进正电子发射断层扫描的抗雄激素疗法

• 批准号: 8555296
• 负责人: Steven Mark Larson
• 金额: $ 22.1万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555296
• 关键词: Adverse effects; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Animals; Antiandrogen Therapy; Biological Markers; Biopsy; Biopsy Specimen; Blood; Cancer Patient; Cells; Clinic; Clinical; Clinical Research; Combined Modality Therapy; Development; Disease; Dose; Exhibits; Gene Expression Profile; Genetically Engineered Mouse; Glycolysis; Goals; Heterogeneity; Hormones; Human; Image; Imaging technology; Individual; LNCaP; Lesion; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Memorial Sloan-Kettering Cancer Center; Molecular; Mus; Mutation; Oncogenic; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phenotype; Positron-Emission Tomography; Radiopharmaceuticals; Receptor Signaling; Research; Research Project Grants; Resistance; Ru-1881; Seizures; Signal Pathway; Staging; Subgroup; Time; Tissue Sample; Tracer; Tumor Tissue; Xenograft Model; abiraterone; base; experience; genetic analysis; genome wide association study; human tissue; in vivo; in vivo Cellular and Molecular Imaging Centers; in vivo Model; inhibitor/antagonist; insight; interest; malignant breast neoplasm; man; molecular imaging; mouse model; next generation; novel; outcome forecast; pre-clinical; radioligand; radiotracer; response; response marker; skills; therapy resistant; treatment response; tumor; uptake

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.

研究项目4（RP 4）的中心主题是改进当前的 在前列腺癌中使用正电子发射断层扫描（PET）作为药效学和预测 抗雄激素治疗期间的生物标志物。在ICMIC-2期间，我们在更多的患者中进行了分子成像（MI）。 使用F-FDHT作为雄激素标志物的100多名去势抵抗性前列腺癌（CRPC）患者 受体（AR）信号传导，和F-FDG作为糖酵解的标志物。我们观察到 病变，其中一些病变仅表现出F-FDG摄取，一些仅表现出F-FDHT摄取，而一些仅表现出F-FDG摄取。 两个追踪器我们还发现，F-FDG摄取（以SUVmax测量）与 CRPC的预后。此外，我们还参与了临床前和早期临床研究。 开发两种令人兴奋的新的下一代抗雄激素（阿比特龙和MDV 3100），Ml 这些研究在帮助优化它们在临床中的使用方面显得非常有希望。在ICMIC-3期间，我们将 利用MI成像研究结果以及从图像引导活检获得的人体组织样本 分析和动物模型，以更好地理解这些Ml表型的分子基础。我们 研究计划包括以下具体目标：SA 1：将F-FDG和F-FDHT成像连接起来 具有潜在遗传改变的人前列腺癌的表型;假设是， 放射性示踪剂F-FDG和V-FDHT标记遗传和代谢上不同的人类亚群 前列腺癌一种新的全基因组分析策略将被使用，我们以前应用 在乳腺癌中取得了成功。SA 2：开发AR-PET放射性配体作为药效学生物标志物 对于新型AR拮抗剂的最佳剂量;假设是AR导向的放射性药物可以 在临床前PCModel中确定AR拮抗剂的饱和剂量，SA 3：探索V-FDG-PET 作为AR靶向治疗期间的早期反应生物标志物;假设成功抑制 单独或在PTEN缺陷细胞中的雄激素受体活性与PI 3 K/mTOR抑制联合， 导致F-FDG摄取减少，作为下一代治疗反应的早期标记 抗雄激素SA 3还将确定在多个时间点进行的V-FDG-PET成像是否 在药物治疗过程中，可以作为对新型AR拮抗剂的反应和耐药性的早期标志物， 人前列腺癌的体内模型。一个独特的共同领导团队丰富了学习计划， 互补的技能，在AR药理学，遗传分析和MI。