Molecular Imaging of Cancer and Its Response to Therapy

这个程序测试分子成像变量，它们如何预测对治疗的反应，以及它们在不同治疗过程中如何变化。我们提出5个互动项目：增殖研究，以验证在各种肿瘤患者中FLT与TdR的比较效果如何，并探索简化PET程序的方法，同时仍然区分通量和转运。我们的假设是，通过适当的数据分析，FLT可以像TdR一样准确地报告肿瘤增殖。我们将验证FLT PET + MRI可以区分最初接受外束放疗加并发TMZ治疗的GBM患者的肿瘤进展和假进展的假设。2. 肿瘤具有不同程度的多药耐药性，从而降低了药物治疗的有效性。我们将通过分析[11C]-维拉帕米动力学，量化p -糖蛋白转运蛋白活性作为治疗耐药和失败的可疑原因。我们将检验新辅助化疗后肿瘤Pgp活性上调的患者生存期和进展时间较短的假设。3. 缺氧是一个重要的阻力因素，使用[18F]-FMISO成像。在患有脑肿瘤的患者中，我们将验证初始手术后的FMISO图像确定局灶增强RT的适当目标，从而缩短肿瘤进展和生存时间的假设。在er阴性转移性乳腺癌患者中，我们将比较缺氧程度对全身治疗的反应和无进展生存期。其他实验将比较FMISO和[64Cu]-ATSM，我们将使用FMISO测试-重测方案和BOLD-MRI来测量时间变化，以寻找肿瘤区域氧合的短期变化。4. 本项目将测试使用18F-FES PET来选择有ER+乳腺癌病史的患者的治疗方案，这些患者先前的治疗方案失败，正在考虑进行补救性内分泌治疗，使用FES PET来测量区域ER作为内分泌治疗的药效学反应，使用FDG PET来定位活动性肿瘤并确定药物治疗的早期效果，包括HER2和ER。该项目还将成像雄激素受体在前列腺癌中的功能，以确定异质AR表达。5. 临床前放射性药物开发和研究。新的方法将被开发成像肿瘤表型的重要方面。有些是新分子；有些是旧分子的新应用；所有这些都是为了开发有前途的显像剂来表征肿瘤表型。其中包括用于治疗乳腺癌的HER2配体，用于雄激素生物学成像的新药物，用于选择前列腺腺癌新临床试验患者的单胺氧化酶a配体，以及比较Cu-ATSM和FMISO不同摄取机制的研究。

This program tests molecular imaging variables, how they predict response to therapy, and how they change over the course of different treatments. We propose 5 interactive projects: 1. Proliferation studies to validate how well FLT compares to TdR in patients with a variety of tumors and explores ways to simplify the PET procedure and still distinguish flux from transport. Our hypothesis is that FLT with appropriate data analysis can be as accurate as TdR for reporting tumor proliferation. We will test the hypothesis that FLT PET plus MRI can distinguish between tumor progression and pseudoprogression in patients with GBM that finish initial therapy with external beam RT plus concurrent TMZ. 2. Tumors have variable levels of multi-drug resistance that reduces effectiveness of drug treatments. We will quantify transporter activity of P-glycoprotein as a suspected cause of treatment resistance and failure by analyzing [11C]-verapamil kinetics. We will test the hypothesis that pts who up-regulate their tumor Pgp activity after neoadjuvant chemotherapy will have shorter survival and time to progression. 3. Hypoxia is an important resistance factor that is imaged using [18F]-FMISO. In pts with brain tumors we will test the hypothesis that FMISO images following initial surgery define an appropriate target for focal boost RT that will improve time to tumor progression and survival. In pts with ER-neg metastatic breast cancer, we will compare the extent of hypoxia to response to systemic therapy and progression-free survival. Other experiments will compare FMISO and [64Cu]-ATSM and we will measure temporal changes using an FMISO test-retest protocol and BOLD-MRI to look for short term changes in regional oxygenation of tumors. 4. This project will test the use of 18F-FES PET to choose therapy in pts with a history of ER+ breast cancer who have failed prior regimens and are being considered for salvage endocrine therapy and use FES PET to measure regional ER as a pharmacodynamic response to endocrine therapy and FDG PET to localize active tumor and identify early effects of drug therapy, including HER2 and ER. The project will also image androgen receptor function in prostate cancer to identify heterogeneous AR expression. 5. Preclinical radiopharmaceutical development and research. New methods will be developed to image important aspects of the tumor phenotype. Some are new molecules; some are new applications for old molecules; all to develop promising imaging agents for characterizing the tumor phenotype. These include ligands for HER2 as a factor in treating breast cancer, new agents for imaging of androgen biology, a monoamine oxidase A ligand to select patients for a new clinical trial for prostate adenocarcinoma and studies comparing Cu-ATSM and FMISO for different mechanisms of uptake.