MULTI-TRACER PET ASSESSMENT OF RESPONSE TO NOVEL TARGETED CHEMOTHERAPY

多示踪剂 PET 评估新型靶向化疗的反应

• 批准号: 8307703
• 负责人: John M Hoffman
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-19 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307703
• 关键词: Acute; Adopted; Advanced Malignant Neoplasm; Adverse effects; Algorithms; Anatomy; BRAF gene; Blood flow; Cancer Patient; Cell Proliferation; Cellular biology; Clinical; Clinical Data; Complex; Cytostatics; Cytotoxic agent; Data; Development; Early treatment; Enrollment; Epidermal Growth Factor Receptor; Erlotinib; Gene Mutation; Genes; Genetic; Gold; Hemorrhage; Human; Image; Imaging Techniques; Injection of therapeutic agent; Laboratories; Life; Link; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Metabolic; Metabolism; Methods; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Monitor; Monoclonal Antibodies; Mutation; Necrosis; Oncogene Deregulation; Outcome; PET/CT scan; Pathway interactions; Patient Care; Patients; Perfusion; Pharmaceutical Preparations; Phase; Pilot Projects; Positron-Emission Tomography; Process; Property; Research; Research Personnel; Resistance; Resistance development; Scanning; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Staging; Techniques; Therapeutic; Therapeutic Clinical Trial; Therapy Clinical Trials; Toxic effect; Tracer; Treatment Failure; Treatment Protocols; Tyrosine Kinase Inhibitor; base; bevacizumab; blood flow measurement; cancer cell; cancer therapy; chemotherapy; clinical practice; drug sensitivity; efficacy testing; fluorodeoxyglucose positron emission tomography; improved; inhibitor/antagonist; kinase inhibitor; melanoma; molecular imaging; novel; oncology; patient population; response; success; therapeutic target; treatment response; tumor; uptake

DESCRIPTION (provided by applicant): Molecular and genetic advancements in understanding cancer cell biology have revealed genes and signaling pathways that regulate proliferation, metastatic potential and chemotherapeutic resistance of cancers. This has led to the development of relatively low-toxicity "targeted chemotherapies" employed in personalized treatment to interrupt signaling pathways expressed by a patient's cancer. Resistance to targeted chemotherapies occurs due to alternate pathways and downstream effects. Transcriptional analysis of resistant tumors may identify additional targeted therapies that can be added to maintain tumor control. Inherent in the success of this approach is the ability to identify early signs of response vs. resistance to single agent targeted chemotherapy. As these drugs are often cytostatic, conventional anatomic imaging to identify early response is typically inadequate. Our preliminary data suggests that FDG PET/CT alone may be inadequate in identifying early treatment failures in certain therapeutic clinical trials. We hypothesize that a multi-tracer molecular imaging profile that employs assessments of metabolic rate (18F-FDG), cellular proliferation [18F-fluorothymidine (FLT)] and blood flow (15O-H2O) will provide an early and more accurate assessment of response vs. resistance to targeted chemotherapies than either single agent PET or anatomic measurements. This imaging response profile may differ as a function of the type of tumors, its genetic or molecular signatures, and the type of targeted chemotherapy employed. We further posit that an imaging approach that requires three separate PET scans for each point in therapeutic assessment and the use of short-lived 15O-H2O to assess blood flow will never be broadly adopted in clinical practice. To overcome this, we hypothesize that the early uptake phase of 18F-FDG or 18F-FLT PET can be used to characterize blood flow, substituting for 15O-H2O. We also hypothesize that serial injections of FDG and FLT with a single dynamic scan can be separated to recover the relevant response measures for each tracer. The specific aims of this project are: Aim 1: To develop a molecular imaging profile of early response and resistance in patients with advanced cancer enrolled in early phase therapeutic trials testing the efficacy of novel single agent targeted chemotherapies. Both at baseline (before treatment) and at 28 days (+/- 4) into treatment, three separate PET/CT scans will be performed utilizing 18F- FDG (metabolism), 18F-FLT (proliferation), and 15O-H2O (blood flow). The initial molecular imaging profile and the changes that occur during the first month of therapy will be compared to anatomic RECIST measurements, molecular signatures, and patient outcome. Aim 2: To extend and apply rapid (single-scan) multi-tracer PET tumor imaging techniques to dual-tracer FDG+FLT imaging of early response and resistance in this patient population, evaluating the feasibility and accuracy of these methods using the clinical scan data acquired under Aim 1. The clinical data will also be used to further validate techniques being developed in our laboratory for characterizing tumor blood flow from the uptake phase of FDG and FLT, using 15O-H2O as a gold standard. PUBLIC HEALTH RELEVANCE: The proposed research will study the concept that multi-tracer PET assessments of response and resistance to novel targeted chemotherapy is feasible and provides important information that improves the care of patients with cancer. This multi-tracer PET imaging approach will improve our understanding of the mechanism of action of these targeted chemotherapeutic drugs by assessing the important biologic properties of tumor metabolism, proliferation, and perfusion.

描述（由申请人提供）：了解癌细胞生物学的分子和遗传进展揭示了调节癌症增殖、转移潜力和化疗耐药性的基因和信号传导途径。这导致了毒性相对较低的“靶向化疗”的发展，用于个性化治疗，以中断患者癌症表达的信号通路。由于替代途径和下游效应，出现了对靶向化疗的耐药性。耐药肿瘤的转录分析可能会识别出额外的靶向疗法，以维持肿瘤控制。这种方法成功的本质是能够识别对单药靶向化疗的早期反应迹象和耐药性。由于这些药物通常具有细胞抑制作用，因此用于识别早期反应的常规解剖成像通常是不够的。我们的初步数据表明，仅 FDG PET/CT 可能不足以识别某些治疗性临床试验中的早期治疗失败。 我们假设一个 采用代谢率 (18F-FDG)、细胞增殖 [18F-氟胸苷 (FLT)] 和血流量 (15O-H2O) 评估的多示踪剂分子成像特征将提供对反应与耐药性的早期且更准确的评估比单一药物 PET 或解剖测量更有针对性的化疗。这种成像反应概况可能因肿瘤类型、其遗传或分子特征以及所采用的靶向化疗类型而异。我们进一步认为，在治疗评估中需要对每个点进行三次单独的 PET 扫描以及使用短命 15O-H2O 来评估血流的成像方法永远不会在临床实践中广泛采用。为了克服这个问题，我们假设 18F-FDG 或 18F-FLT PET 的早期摄取阶段可用于替代 15O-H2O 来表征血流。我们还假设可以将单次动态扫描的 FDG 和 FLT 连续注射分开，以恢复每个示踪剂的相关响应措施。该项目的具体目标是： 目标 1：开发参与早期治疗试验的晚期癌症患者早期反应和耐药的分子成像特征，测试新型单药靶向化疗的疗效。在基线（治疗前）和治疗第 28 天 (+/- 4) 时，将利用 18F-FDG（代谢）、18F-FLT（增殖）和 15O-H2O（血液）进行三次单独的 PET/CT 扫描。流动）。初始分子成像概况和治疗第一个月期间发生的变化将与解剖 RECIST 测量、分子特征和患者结果进行比较。目标 2：将快速（单次扫描）多示踪剂 PET 肿瘤成像技术扩展到该患者群体早期反应和耐药的双示踪剂 FDG+FLT 成像，并使用临床扫描评估这些方法的可行性和准确性目标 1 下获得的数据。临床数据还将用于进一步验证我们实验室正在开发的技术，该技术使用 15O-H2O 作为黄金来表征 FDG 和 FLT 摄取阶段的肿瘤血流 标准。 公共健康相关性：拟议的研究将研究多示踪剂 PET 评估新型靶向化疗的反应和耐药性的可行性，并提供改善癌症患者护理的重要信息。这种多示踪剂 PET 成像方法将通过评估肿瘤代谢、增殖和灌注的重要生物学特性，提高我们对这些靶向化疗药物作用机制的理解。