MULTI-TRACER PET ASSESSMENT OF RESPONSE TO NOVEL TARGETED CHEMOTHERAPY

描述（由申请人提供）：在了解癌细胞生物学方面的分子和遗传学进展揭示了调节癌症增殖、转移潜能和化疗耐药性的基因和信号通路。这导致了相对低毒的“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。对靶向化疗的耐药是由于替代途径和下游效应。对耐药肿瘤的转录分析可以确定额外的靶向治疗，以维持肿瘤控制。这种方法的成功之处在于能够识别单药靶向化疗的早期反应和耐药迹象。由于这些药物通常是细胞抑制剂，常规的解剖成像来识别早期反应通常是不充分的。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a

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.