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: 8513947
• 负责人: John M Hoffman
• 金额: $ 29.99万
• 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/8513947
• 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; tumor metabolism; 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.

描述(申请人提供)：在了解癌细胞生物学方面的分子和遗传进展揭示了调节癌症的增殖、转移潜能和化疗耐药性的基因和信号通路。这导致了毒性相对较低的“靶向化疗”的发展，这种疗法用于个性化治疗，以阻断患者癌症表达的信号通路。对靶向化疗的耐药性是由于替代途径和下游效应造成的。对耐药肿瘤的转录分析可能会确定可以增加的其他靶向治疗，以维持肿瘤控制。这种方法成功的内在原因是能够识别单药靶向化疗的反应和耐药性的早期迹象。由于这些药物通常是细胞抑制的，传统的解剖成像通常不足以识别早期反应。我们的初步数据表明，在某些治疗临床试验中，仅靠FDG PET/CT可能不足以识别早期治疗失败。我们假设一个 采用代谢率(18F-FDG)、细胞增殖[18F-氟代胸苷(Flt)]和血流(150-H2O)评估的多示踪分子成像图谱将比单剂PET或解剖测量提供更早和更准确的靶向化疗反应与耐药性评估。根据肿瘤的类型、其基因或分子特征以及所采用的靶向化疗的类型，这种成像反应谱可能有所不同。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扫描并使用短暂的15O-H2O来评估血流的成像方法将永远不会在临床实践中广泛采用。为了克服这一点，我们假设18F-FDG或18F-Flt PET的早期摄取阶段可以用来表征血流，取代15O-H2O。我们还假设，连续注射FDG和Flt与单次动态扫描可以分开，以恢复每个示踪剂的相关反应措施。本项目的具体目标是：目标1：建立参加早期治疗试验的晚期癌症患者的早期反应和耐药的分子成像图谱，测试新型单药靶向化疗的疗效。在基线(治疗前)和治疗后28天(+/-4)，将分别进行三次PET/CT扫描，分别使用18F-FDG(代谢)、18F-Flt(增殖)和15O-H2O(血流)。最初的分子成像特征和治疗第一个月期间发生的变化将与解剖RECIST测量、分子签名和患者结果进行比较。目的2：将快速(单次扫描)多示踪PET肿瘤成像技术扩展和应用于该患者群体的早期反应和耐药性的双示踪FDG+Flt成像，使用Aim 1获得的临床扫描数据评估这些方法的可行性和准确性。临床数据还将用于进一步验证我们实验室正在开发的以15O-H2O为金标准的从FDG和Flt摄取阶段的肿瘤血流特征的技术。