MULTI-TRACER PET ASSESSMENT OF RESPONSE TO NOVEL TARGETED CHEMOTHERAPY

描述（由申请人提供）：在理解癌细胞生物学方面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通路。这导致了在个性化治疗中使用的相对低毒性的“靶向化疗”的发展，以中断由患者癌症表达的信号传导途径。对靶向化疗的耐药性是由于替代途径和下游效应而发生的。耐药肿瘤的转录分析可以确定可以添加以维持肿瘤控制的其他靶向治疗。这种方法成功的内在原因是能够识别对单一药物靶向化疗的反应与耐药性的早期迹象。由于这些药物通常是细胞抑制性的，因此常规的解剖成像来识别早期反应通常是不够的。我们的初步数据表明，在某些治疗性临床试验中，单独使用FDG PET/CT可能不足以识别早期治疗失败。 我们假设 采用代谢率（18 F-FDG）、细胞增殖[18 F-氟胸苷（FLT）]和血流（15 O-H2O）评估的多示踪剂分子成像谱将提供比单药PET或解剖测量更早和更准确的靶向化疗反应与耐药性评估。这种成像反应谱可能因肿瘤类型、其遗传或分子特征以及所采用的靶向化疗类型而不同。我们进一步证实，在治疗评估中需要对每个点进行三次单独的PET扫描以及使用短寿命的15 O-H2O来评估血流的成像方法将永远不会在临床实践中被广泛采用。为了克服这一点，我们假设18F-FDG或18F-FLT PET的早期摄取阶段可用于表征血流，替代15 O-H2O。我们还假设，连续注射FDG和FLT与一个单一的动态扫描可以分开，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：开发晚期癌症患者的早期反应和耐药的分子成像特征，这些患者参加了早期治疗试验，以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），将使用18F-FDG（代谢）、18F-FLT（增殖）和15 O-H2O（血流）进行三次单独的PET/CT扫描。将初始分子成像特征和治疗第一个月期间发生的变化与解剖学RECIST测量值、分子特征和患者结局进行比较。目标二：将快速（单次扫描）多示踪剂PET肿瘤成像技术扩展并应用于该患者人群的早期反应和抵抗的双示踪剂FDG+FLT成像，使用目标1下采集的临床扫描数据评价这些方法的可行性和准确性。临床数据也将用于进一步验证我们实验室正在开发的技术，用于表征FDG和FLT摄取阶段的肿瘤血流，使用15 O-H2O作为金标准。 公共卫生相关性：拟议的研究将研究多示踪剂PET评估对新型靶向化疗的反应和抵抗是可行的，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。

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.