Ascorbate-based biomarkers for predicting radiation response in prostate cancer

基于抗坏血酸的生物标志物用于预测前列腺癌的放射反应

• 批准号: 8627148
• 负责人: David M Wilson
• 金额: $ 48.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-24 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627148
• 关键词: Address; Adenocarcinoma; Antioxidants; Ascorbic Acid; Behavior; Bicarbonates; Biochemical; Biological Markers; Biopsy; Bioreactors; Brain; Brain Neoplasms; Cancer Patient; Cells; Characteristics; Chemical Structure; Clinic; Clinical; Comparative Study; Complement; Coupled; Data; Dehydroascorbic Acid; Development; Diagnosis; Disease; Equilibrium; Failure; Fructose; Fumarates; Generations; Glucose; Glucose Transporter; Glutathione; Glutathione Reductase; Glycine; Hexoses; Human; Image; Imaging Techniques; In Vitro; Infusion procedures; Kidney; Label; Laboratories; Lactate Dehydrogenase; Literature; Liver; Liver neoplasms; Magic; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolism; Methods; Modality; Modeling; Molecular; Molecular Probes; Motivation; Mus; NADP; Necrosis; Nuclear; Oncogenic; Organ; Oxidation-Reduction; PC3 cell line; Pathologic; Patients; Physiological Processes; Positron-Emission Tomography; Prostate; Prostatic Neoplasms; Pyruvate; Radiation; Radiation therapy; Radioisotopes; Reaction; Reactive Oxygen Species; Reporting; Resistance; Resolution; SLC2A1 gene; Signal Transduction; Spectrum Analysis; Techniques; Technology; Therapeutic; Tissues; Transgenic Organisms; Translations; Treatment Protocols; Validation; Work; ascorbate; base; chemical reduction; chemotherapy; cytotoxic; dehydroascorbate; glutaredoxin; imaging modality; improved; in vivo; malignant breast neoplasm; molecular imaging; pre-clinical therapy; prostate cancer cell; prostate cancer model; rapid detection; response; sensor; therapy resistant; treatment planning; treatment response; tumor; uptake

DESCRIPTION (provided by applicant): Remarkable progress has been made over the last decade in the characterization of in vivo metabolism using hyperpolarized (HP) 13C spectroscopy, with profound implications for the diagnosis and treatment of human cancers. The majority of studies have focused on metabolism of [1-13C] pyruvate by lactate dehydrogenase (LDH), which occurs to a larger extent in cancer and has been correlated with pathologic grade in a murine prostate tumor model. Although the molecular requirements of dynamic nuclear polarization (DNP) are rather strict, several additional hyperpolarized 13C agents have been developed that are potential markers for pH (13C bicarbonate), hexose metabolism ([2-13C] fructose), and necrosis ([1,4-13C] fumarate). More recently, we have developed the redox sensor [1-13C] dehydroascorbate (DHA), an oxidized version of Vitamin C that shares an uptake mechanism with glucose. This new probe demonstrates rapid in vivo reduction to [1-13C] Vitamin C, and is the principal agent used for the Specific Aims of this R01 proposal. In the proposed project, this new probe is employed to address the redox adaptation of tumors, which accumulate large quantities of GSH and other antioxidants, conferring resistance to therapies that are ROS- dependent, including radiation. Prostate cancer was chosen since (1) radiation therapy is a mainstay of treatment (2) several in vitro studies have implicated GSH and other redox components in resistance and (3) non-invasive biomarkers for disease aggressiveness are lacking. Our preliminary 1H studies on primary prostate cancer cells using high resolution magic-angle spinning (HR-MAS) NMR indicate high levels of GSH, and in vivo murine studies using HP [1-13C] DHA demonstrate reduction in organs that are known to be rich in GSH, including the liver, kidneys, and brain. Furthermore, numerous reports in the literature have established that reduction of DHA to VitC is GSH-mediated. However, other redox mechanisms are certainly possible for the reduction of HP [1-13C] DHA observed in vivo, and our first studies will determine which cellular redox (or transport) components are involved (Specific Aim 1). We will then turn to studies validating the use of HP [1- 13C] DHA to determine cancer aggressiveness, and predict response to radiation therapy in a murine prostate cancer (TRAMP) model (Specific Aim 2). Finally, we will compare this new 13C probe to related 18F ascorbates as well as to [2-deoxy-2-18F] fluoro-D-glucose (FDG), the radioisotope used in the vast majority of clinical positron emission tomography (PET) studies (Specific Aim 3). We anticipate HP 13C MRI emerging as an important technology to complement existing molecular imaging methods, including PET, and comparative studies (employing structurally or mechanistically related probes) will be important to validate both modalities. Our justification for pursuing 18F ascorbate probes is twofold: (1) to determine whether ascorbate-based PET probes demonstrate similar in vivo characteristics to HP [1-13C] DHA and (2) to compare the ability of PET and HP methods to predict tumor aggressiveness/ treatment response in prostate cancer.

描述（由申请人提供）：在过去的十年中，在使用超极化（HP）13C光谱的体内代谢表征中取得了显着进步，对人类癌症的诊断和治疗产生了深远的影响。大多数研究都集中在乳酸脱氢酶（LDH）的[1-13c]丙酮酸的代谢上，该脱氢酶在癌症的范围内较大，并且与鼠前列腺肿瘤模型中的病理级相关。尽管动态核极化（DNP）的分子需求相当严格，但已经开发了几种其他超极化13C剂，它们是pH（13c碳酸氢盐），己糖代谢（[2-13C]果糖）和坏死（[[1,4-13c] fumarate）的潜在标记。最近，我们开发了氧化还原传感器[1-13C]脱氢剂（DHA），这是一种氧化的维生素C，具有带有葡萄糖的吸收机制。该新的探针表明体内快速降低至[1-13C]维生素C，并且是用于该R01提案的特定目的的主要药物。在拟议的项目中，该新的探针用于解决肿瘤的氧化还原适应，该肿瘤累积了大量的GSH和其他抗氧化剂，从而赋予了对依赖于ROS的疗法的耐药性，包括辐射。选择了前列腺癌，因为（1）放射治疗是治疗的主要支柱（2）几项体外研究已牵涉GSH，而其他氧化还原成分则具有耐药性，并且（3）缺乏疾病侵略性的非侵入性生物标志物。我们使用高分辨率魔法旋转（HR-MAS）NMR对原发性前列腺癌细胞进行初步研究表明，使用HP [1-13C] DHA的体内鼠研究表明，在包括肝脏，肾脏和大脑在内的GSH中富含GSH的器官的降低表明，该器官的降低。此外，文献中的许多报道已经确定，将DHA减少到VITC是GSH介导的。但是，在体内观察到的HP [1-13C] DHA的减少肯定是可能的，我们的第一批研究将确定涉及哪些细胞氧化还原（或运输）成分（特定目标1）。然后，我们将研究验证使用HP [1-13C] DHA来确定癌症侵袭性的研究，并预测鼠前列腺癌（Tramp）模型中对放射治疗的反应（特定目标2）。最后，我们将将这一新的13C探针与相关的18F抗坏血酸酯以及[2-脱氧-2-18F]氟-D-葡萄糖（FDG）（绝大多数临床正电子发射断层扫描（PET）研究中使用的放射性同位素（特定目标3）。我们预计，HP 13C MRI作为补充现有的分子成像方法的重要技术，包括PET和比较研究（在结构或机械上相关的探针）对于验证这两种模态将很重要。我们追求18F抗坏血酸的理由 探针是双重的：（1）确定基于抗坏血酸的PET探针是否表现出与HP [1-13C] DHA和（2）比较PET和HP方法预测前列腺癌中肿瘤侵袭/治疗反应的能力的体内特征。