Real Time Metabolic Imaging to Interrogate Early Detection and Prevention of Pancreatic Cancer

实时代谢成像探讨胰腺癌的早期检测和预防

• 批准号: 10744576
• 负责人: Jose S Enriquez
• 金额: $ 3.72万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744576
• 关键词: Alanine; Anatomy; Animal Model; Animals; Area; Biochemical; Biological Markers; Biology; Cancer Center; Cancer Detection; Cancer Etiology; Cessation of life; Clinical; Contrast Media; Cyst; Data Analyses; Detection; Development; Diagnosis; Disease; Disease Progression; Doctor of Medicine; Doctor of Philosophy; Early Diagnosis; Educational process of instructing; Fellowship; Future; Genetic Models; Genetically Engineered Mouse; Genomics; Goals; Histological Techniques; Image; Imaging Techniques; Immunoprevention; Immunotherapy; Indolent; Inflammation; Institution; Laboratories; Learning; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mentors; Metabolic; Metabolism; Methodology; Methods; Modality; Modeling; Monitor; Morphology; Non-Invasive Detection; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pattern; Phase; Positron-Emission Tomography; Postdoctoral Fellow; Prevalence; Prevention; Prevention Measures; Prevention strategy; Production; Public Speaking; Pyruvate; Recommendation; Research; Research Project Grants; Research Proposals; Scientist; Sensitivity and Specificity; Signal Transduction; Specificity; Survival Rate; Symptoms; Techniques; Time; Tissues; Training; Translating; United States; Warburg Effect; Work; Writing; cancer imaging; cancer prevention; cancer type; chronic pancreatitis; detection method; efficacy evaluation; efficacy testing; extracellular; high risk; human subject; imaging approach; imaging modality; imaging system; in vivo; in vivo imaging; innovation; metabolic imaging; metabolomics; molecular imaging; mouse model; neoplastic; non-invasive imaging; non-invasive monitor; novel; overtreatment; pancreatic cancer model; pancreatic ductal adenocarcinoma model; pre-clinical; premalignant; prevent; skills; specific biomarkers; success; tool; transcriptomics; tumor; tumor microenvironment

Project Summary Pancreatic ductal adenocarcinoma (PDAC) has a median 5-year survival of only 11%, and early diagnosis of PDAC is recognized as one of the highest priority areas by the NCI, with a focus on identification of more sensitive and specific biomarkers and imaging strategies in discernible preneoplastic lesions. The overarching goal of this proposal is to develop the capability of non-invasively detecting advanced pancreatic intraepithelial neoplasia (PanIN) precursor lesions in pancreas prior to invasive disease in human subjects using two magnetic resonance imaging-based tools: a) hyperpolarized metabolic imaging (HP MR) and b) acidoCEST MRI. Hyperpolarization increases the signal of conventional MRI by over 10,000-fold. AcidoCEST MRI uses a clinically approved contrast agent to quantitatively measure the extracellular pH (pHe) in the tumor microenvironment. The application of dual acidoCEST and HP MR is innovative as they interrogate two different but related biochemical features of PanINs: extracellular pH (pHe) and dynamic metabolic flux (HP lactate-to- pyruvate and HP alanine-to-pyruvate ratios), respectively. Together, this approach provides an exciting opportunity to identify and understand early metabolic aberrations and biomarkers associated with these early lesions, to enable detection of advanced pancreatic preneoplastic lesions as well as pancreatic cancer at the smallest size, for which no methods of detection currently exist. This is a transitional research proposal with multiple sponsors for the F99 phase. Including the laboratories of Pratip Bhattacharya, Ph.D. in the Department of Cancer Systems Imaging and Florencia McAllister, M.D. in the Department of Clinical Cancer Prevention, both at MD Anderson Cancer Center with the following two aims. Aim 1, the F99 phase, is to demonstrate and validate the sensitivity and specificity of dynamic hyperpolarized metabolic biomarkers in the detection and monitoring the progression of pancreatic premalignant lesions to PDAC and compare these to a chronic pancreatitis model. Aim 2, the K00 phase research direction, is to demonstrate detection of PanIN with a combination of HP MR and acidoCEST and to determine the efficacy of immunoprevention on PanIN models. The success of this proposal has the potential for leading to practice changing recommendations for non-invasively detecting and monitoring advanced PanIN lesions and incipient pancreatic cancer, as well as to non-invasively assess the immunopreventive measures for cancer prevention. Also included in this proposal is a fellowship training plan to be conducted in both the F99 and K00 phases. They include additional training in metabolomic data analysis, research skills in small animal handling, histological and imaging techniques, public speaking, and scientific writing during the F99 phase. For the K00 phase the training plan include establishing dual-imaging modalities, develop immunopreventative strategies, mentoring and teaching future scientists, and inter-departmental or institutional networking.

项目概要 胰腺导管腺癌 (PDAC) 的中位 5 年生存率仅为 11%，并且早期 PDAC 的诊断被 NCI 视为最优先领域之一，重点是识别 在可辨别的癌前病变中更敏感、更特异的生物标志物和成像策略。这 该提案的总体目标是开发非侵入性检测晚期胰腺的能力 使用人类受试者的侵袭性疾病之前的胰腺上皮内瘤变（PanIN）前体病变 两种基于磁共振成像的工具：a) 超极化代谢成像 (HP MR) 和 b) AcidoCEST 核磁共振成像。超极化可将传统 MRI 的信号增强 10,000 倍以上。 AcidoCEST MRI 使用 临床批准的造影剂，用于定量测量肿瘤中的细胞外 pH (pHe) 微环境。双 AcidoCEST 和 HP MR 的应用是创新的，因为它们询问两种不同的 但 PanIN 的相关生化特征：细胞外 pH (pHe) 和动态代谢通量（HP 乳酸- 分别为丙酮酸和 HP 丙氨酸与丙酮酸的比率）。总之，这种方法提供了令人兴奋的 有机会识别和了解早期代谢异常以及与这些早期代谢异常相关的生物标志物 病变，以便能够检测晚期胰腺癌前病变以及胰腺癌 最小尺寸，目前尚无检测方法。 这是一项针对 F99 阶段的过渡性研究提案，有多个赞助商。包括 Pratip Bhattacharya 博士的实验室在癌症系统成像和弗洛伦西亚系 McAllister，医学博士，临床癌症预防科，均在 MD 安德森癌症中心与 以下两个目标。目标 1（F99 阶段）是展示和验证动态分析的敏感性和特异性 超极化代谢生物标志物在检测和监测胰腺癌前病变进展中的应用 PDAC 损伤并将其与慢性胰腺炎模型进行比较。目标2，K00阶段研究方向， 旨在证明结合 HP MR 和 AcidoCEST 检测 PanIN 并确定功效 PanIN 模型上的免疫预防。该提案的成功有可能付诸实践 改变非侵入性检测和监测晚期 PanIN 病变和初期病变的建议 胰腺癌，以及非侵入性评估癌症预防的免疫预防措施。 该提案还包括将在 F99 和 K00 中进行的奖学金培训计划 阶段。其中包括代谢组数据分析、小动物处理研究技能的额外培训， F99 阶段的组织学和成像技术、公开演讲和科学写作。对于K00 培训计划阶段包括建立双成像模式、制定免疫预防策略、 指导和教授未来的科学家，以及跨部门或机构的网络。