Imaging Therapeutic Targets

该项目将继续进行成像治疗靶点的工作，以选择适当的癌症治疗方法，并成像所选药物对治疗靶点的影响。在之前的资助期间，我们使用[18]氟雌二醇(FES)PET在乳腺癌雌激素受体(ER)成像方面取得了进展。此次更新将使用FES PET来测量局部ER作为乳腺癌内分泌治疗的药物动力学反应，并使用FDG PET来定位活跃的肿瘤部位，并确定药物治疗对包括HER2和ER在内的生长因子途径的早期影响。我们还将把受体靶点的成像扩展到前列腺癌。 目的1：我们将测试FES PET的使用，以帮助有ER+乳腺癌病史的患者选择治疗，这些患者以前的治疗方案失败，正在考虑挽救内分泌治疗。我们先前的经验表明，低FES摄取率强烈预示着对内分泌治疗缺乏反应。在同一组中，我们将测试使用FES作为预测标记物是否导致与来自类似患者的历史数据相比，FES作为预测标记物的应答率增加，在类似患者中，FES成像是纯粹观察性的。 目的：用FES-PET和FDG-PET预测内分泌治疗联合其他靶向药物的疗效。系列FES/FDG PET将用于测量联合治疗的药效学(PD)。对于ER+和HER2过度表达的肿瘤患者，将使用成像来评估抗HER2治疗对ER表达的影响(FES PET)和联合治疗的早期反应(FDG PET)。我们还将探索使用组蛋白脱乙酰酶(HDAC)抑制剂在内分泌治疗无效的乳腺癌肿瘤中重新表达ER的治疗方法。在治疗前和治疗14天后，分别进行FES和FDGPET检查，然后进行HDAC抑制剂/芳香酶抑制剂联合治疗，以验证治疗成功可以通过ER表达增加来衡量的假设。 目的3：建立前列腺癌激素功能的成像方法。内分泌治疗仍然是前列腺癌患者的重要一线治疗。我们将评估雄激素受体靶向显像剂，从FDHT开始，但如果临床前试验令人鼓舞，则继续从项目5开始使用新的显像剂。正如我们早期对乳腺癌ER成像的研究一样，最初的重点将是完善图像采集和分析的方法，包括新陈代谢和蛋白质结合，以及激素难治性疾病。

This project will continue work on imaging therapeutic targets to choose appropriate cancer therapy and image the effect of the chosen drug on the therapeutic targets. During the previous funding period we made progress in imaging estrogen receptors (ER) in breast cancer, using [18]F-fluoroestradiol (FES) PET. The renewal will use FES PET to measure regional ER as a pharmaco-dynamic response of breast cancer endocrine therapy and FDG PET to localize active tumor sites and to identify early effects of drug therapy on growth factor pathways including HER2 and ER. We will also extend our imaging of receptor targets to prostate cancer. Aim 1: We will test the use of FES PET to help choose therapy in patients with a history of ER+ breast cancer who have failed prior regimens and are being considered for salvage endocrine therapy. This is a group where our prior experience showed that low FES uptake strongly predicted a lack of response to endocrine therapy. In this same group, we will test whether the use of FES as a predictive marker results in an increased response rate compared to historical data from similar patients where FES imaging was purely observational. Aim 2: Use FES PET and FDG PET to predict response to endocrine treatment combined with other targeted agents. Serial FES/FDG PET will be used to measure the pharmacodynamics (PD) of combined therapy. For patients with ER+ and HER2 over-expressing tumors, imaging will be used to assess the effect of anti-HER2 treatment on ER expression (FES PET) and early response to combined therapy (FDG PET). We will also explore therapy to re-express ER in breast cancer tumors refractory to endocrine therapy using a histone deacetylase (HDAC) inhibitor. FES and FDG PET will be performed prior to therapy and after 14 days of HDAC inhibitor therapy alone, followed by combined HDAC inhibitor/aromatase inhibitor therapy to test the hypothesis that successful therapy can be measured by an increase in ER expression. Aim 3: Develop methods to image hormonal function in prostate cancer. Endocrine therapy continues to be an important first line in prostate cancer patients. We will evaluate androgen receptor-targeted imaging agents, starting with FDHT, but continuing to new agents from project 5 if preclinical trials are encouraging. As in our early studies of ER imaging in breast cancer, the initial focus will be on refining the approaches to image acquisition and analysis, including metabolism and protein binding, and on hormone-refractory disease.