The Development of Radiolabeled Positional isomers of [11C]Pyruvate for Imaging Cancer Metabolism

用于癌症代谢成像的[11C]丙酮酸放射性标记位置异构体的开发

基本信息

批准号：
10057979
负责人：
James Kelly
金额：
$ 25.14万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057979
关键词：
Acetyl Coenzyme A Address Alanine Androgen Receptor Androgens Area Under Curve Biochemical Biological Markers Carbon Carbon Dioxide Cell Count Cells Clinic Couples D-Amino Acid Dehydrogenase Development Diagnosis Diagnostic Disease Enzymes Evaluation Exhibits Gap Junctions Glucose Half-Life Image Imaging Techniques Indolent Isomerism LNCaP Label Malignant Neoplasms Malignant neoplasm of prostate Measures Metabolic Metabolic Clearance Rate Metabolic Pathway Metabolism Methods Mitochondria Molecular Monitor Mus Normal Cell Normal tissue morphology Oxides PC3 cell line Patient-Focused Outcomes Patients Phase Phenotype Phosphorylation Positioning Attribute Positron-Emission Tomography Procedures Production Pyruvate Pyruvate Metabolism Pathway Radioactivity Radiolabeled Receptor Signaling Resistance Resistance development Resolution Reverse Transcriptase Polymerase Chain Reaction Solid Solvents Staging Stains Time Tissues Tracer Translations Variant Warburg Effect Western Blotting Work Xenograft Model androgen sensitive cancer cell cancer diagnosis cancer imaging clinical imaging clinically relevant deprivation expectation fluorodeoxyglucose glucose analog imaging biomarker improved kinetic model mRNA Expression magnetic resonance spectroscopic imaging men metabolic phenotype molecular imaging new therapeutic target outcome forecast overexpression oxidation pre-clinical prostate cancer cell prostate cancer cell line prostate cancer model radiotracer receptor response screening small molecule therapy resistant tool tumor tumor metabolism tumor xenograft uptake

项目摘要

The objectives of screening and diagnostic strategies in cancer are to detect disease within the window of curability and avoid over- and under-treatment. The discovery of imaging biomarkers that improve the identification of aggressive versus non-aggressive variants of disease would enhance our ability to treat patients appropriately. In contrast to normal cells, cancer cells typically reduce pyruvate to lactate, a phenomenon known as the Warburg effect. This altered metabolism provides an opportunity to distinguish tumors from healthy tissue by non-invasive molecular imaging. Increased demand for glucose by metabolically reprogrammed cancer cells is exploited by positron emission tomography (PET) imaging using [18F]fluorodeoxyglucose, [18F]FDG, which typically delineates tumors with high sensitivity. Prostate cancer (PCa), however, does not typically exhibit the Warburg effect, and [18F]FDG uptake in PCa is low. Alternative biomarkers to [18F]FDG would be valuable tools with which to diagnose and stage PCa, the most frequently diagnosed cancer in men in the US. As PCa develops resistance to therapies that block androgen receptor (AR) signaling, it transitions to a glycolytic phenotype characterized by reduction of pyruvate to lactate. Pyruvate is at the nexus of cellular metabolism, and is therefore an attractive candidate for imaging cancer metabolism by PET. Carbon-11-labeled pyruvate couples the advantages of PET, including enhanced sensitivity and biochemical resolution, to an essential metabolite whose specific metabolic fate has important implications for disease staging and prognosis, monitoring therapy, and identifying new therapeutic targets. We propose to label pyruvate with carbon-11 at either the C-1 position ([1- 11C]pyruvate) or the C-3 position ([3-11C]pyruvate). By labeling this simple molecule at different positions, it will be possible to infer the metabolic fate of pyruvate and therefore determine the aggressiveness of PCa tumors. Current syntheses of these molecules are inadequate for imaging needs. The automated synthesis of [1-11C]- and [3-11C]pyruvate via D-[11C]alanine is the first aim of this proposal. We will evaluate [1-11C]- and [3- 11C]pyruvate flux in two preclinical xenograft models of PCa: androgen-sensitive LNCaP, which we expect to predominantly oxidize pyruvate to acetyl-CoA and CO2, and androgen-insensitive, N-Myc overexpressing PC3, which we expect to predominantly reduce pyruvate to lactate. We hypothesize that the clearance of radioactivity from LNCaP tumors will be significantly faster following administration of [1-11C]pyruvate than following administration of [3-11C]pyruvate. By contrast, we expect the clearance rates to be similar in PC3 tumors. Finally, we will exploit known metabolic differences in PCa cell lines to measure the metabolic fate of pyruvate in the presence or absence of androgens. Our expectation is that aggressiveness and AR signaling blockade will be associated with elevated levels of phospho-Akt, N-Myc, and LDHA, and consequently increased reduction of pyruvate to lactate. On this basis, we aim to validate [1-11C]- and [3-11C]pyruvate as imaging biomarkers of cancer metabolism and tools for non-invasive assessment of tumor aggressiveness.

癌症筛查和诊断策略的目标是在窗口内检测疾病的治愈性并避免过度和治疗不足。成像生物标志物的发现可以改善识别疾病的侵袭性与非侵袭性变异将增强我们治疗患者的能力适当地。与正常细胞相反，癌细胞通常将丙酮酸还原为乳酸，这是一种已知的现象正如瓦尔堡效应。这种代谢的改变提供了区分肿瘤和健康组织的机会通过非侵入性分子成像。代谢重编程的癌细胞对葡萄糖的需求增加利用[18F]氟脱氧葡萄糖、[18F]FDG 进行正电子发射断层扫描 (PET) 成像，通常以高灵敏度描绘肿瘤。然而，前列腺癌 (PCa) 通常不会表现出 Warburg 效应，PCa 中的 [18F]FDG 摄取较低。 [18F]FDG 的替代生物标志物将是有价值的工具用于诊断前列腺癌并对其进行分期，前列腺癌是美国男性中最常诊断出的癌症。随着 PCa 的发展对阻断雄激素受体 (AR) 信号传导的治疗产生耐药性，它会转变为糖酵解表型其特征在于丙酮酸还原为乳酸。丙酮酸是细胞代谢的纽带，因此是通过 PET 对癌症代谢进行成像的有吸引力的候选者。碳 11 标记的丙酮酸偶联 PET 的优点，包括增强的敏感性和生化分辨率，对一种重要的代谢物，其特定的代谢命运对于疾病分期和预后、监测治疗以及确定新的治疗靶点。我们建议在 C-1 位置（[1- 11C]丙酮酸）或C-3位置（[3-11C]丙酮酸）。通过在不同位置标记这个简单的分子，它将可以推断丙酮酸的代谢命运，从而确定 PCa 肿瘤的侵袭性。目前这些分子的合成不足以满足成像需求。 [1-11C]-的自动合成和通过D-[11C]丙氨酸的[3-11C]丙酮酸是该提案的首要目标。我们将评估 [1-11C]- 和 [3- 11C]两种 PCa 临床前异种移植模型中的丙酮酸通量：雄激素敏感的 LNCaP，我们预计主要将丙酮酸氧化为乙酰辅酶A和CO2，以及雄激素不敏感、N-Myc过表达PC3，我们预计这主要是将丙酮酸还原为乳酸。我们假设放射性的清除给予[1-11C]丙酮酸后，LNCaP 肿瘤的生长速度明显快于以下 [3-11C]丙酮酸的施用。相比之下，我们预计 PC3 肿瘤中的清除率相似。最后，我们将利用 PCa 细胞系中已知的代谢差异来测量丙酮酸在 PCa 细胞系中的代谢命运。存在或不存在雄激素。我们的预期是攻击性和 AR 信号封锁将会与磷酸-Akt、N-Myc 和 LDHA 水平升高相关，从而增加丙酮酸转化为乳酸。在此基础上，我们的目标是验证[1-11C]-和[3-11C]丙酮酸作为癌症的成像生物标志物代谢和非侵入性评估肿瘤侵袭性的工具。