Cellular Proliferation is a Robust Pharmacodynamic Endpoint

细胞增殖是一个强有力的药效终点

• 批准号: 8566990
• 负责人: ALEXANDER M SPENCE
• 金额: $ 14.06万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8566990
• 关键词: 2' -Deoxythymidine; Acute Myelocytic Leukemia; Aftercare; Biological Assay; Blood; Blood Volume; Blood flow; Blood specimen; Brain Neoplasms; Cancer Patient; Carcinoma; Cell Proliferation; Central Nervous System Neoplasms; Cerebrum; Choline; Clinical; Complex; Coupled; Creatine; Cytostatics; DNA; DNA biosynthesis; Data; Data Analyses; Data Set; Development; Diagnosis; Diffusion; External Beam Radiation Therapy; Glioblastoma; Glioma; Growth; Hematologic Neoplasms; Histocompatibility Testing; Histology; Hour; Image; Image Analysis; Imaging Techniques; Imaging problem; Immunotherapy; Inflammation; Kinetics; Label; Literature; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measurable Disease; Measures; Metabolic; Metabolism; Methods; Modeling; N-acetylaspartate; Necrosis; New Agents; Newly Diagnosed; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmacodynamics; Phase II Clinical Trials; Physiological; Positron-Emission Tomography; Procedures; Protocols documentation; Publishing; Radiation therapy; Recovery of Function; Regional Perfusion; Renal Sarcoma; Renal carcinoma; Reporting; Research; Risk; Sampling; Site; Solid Neoplasm; Step Tests; Techniques; Testing; Thymidine; Tissues; Tracer; Validation; Venous; Venous blood sampling; Work; arm; base; cancer type; chemotherapy; gastrointestinal carcinoma; improved; leukemia; mathematical model; molecular imaging; novel; programs; response; sarcoma; standard care; temozolomide; thymidine kinase 1; tumor; tumor growth; tumor progression; uptake

Proliferation imaging has been a focus of this program since it started, initially with [2-[11]C]-thymidine (TdR) which is incorporated into DNA; later with our introduction of [[18]F]-FLT (FLT). The rate of DNA synthesis via the salvage pathway provides a robust approach for estimating growth rate of tumors and changes in response to treatment. A simple FLT{suv} does not reliably indicate cellular proliferation. Further work is essential to validate how well FLT measures cellular proliferation compared to TdR. Our application of these two tracers requires dynamic imaging with blood sampling and mathematical modeling to separate flux (retention) of the tracers from transport. It is also worthwhile to explore simpler ways to acquire the important parametric data more simply with image-based arterial input functions and a minimal number of venous samples for calibrating the input functions and assaying for metabolites. Generalize: We have published analytical approaches for TdR and FLT in brain tumors and will now generalize this to other tumor sites, directly comparing TdR and FLT to determine whether flux and transport of FLT provides measures as accurately indicative of cellular proliferation as those of TdR. Specifically, we will compare these two tracers in patients with glioma, leukemia, sarcoma, renal, and Gl carcinomas before and after therapy. Our hypothesis is that FLT with appropriate data analysis can be as accurate as TdR for reporting tumor proliferation and response to therapy. Simplify: Our approach to simplifying the PET procedure will evaluate with minimal venous sampling to identify labeled metabolites. Our hypothesis is that the accuracy of flux and transport estimates can be maintained using simplified procedures. Progression or not? Standard therapy for newly diagnosed glioblastoma multiforme is 60 Gy RT plus concurrent temozolomide (TMZ) chemotherapy. From 9 to 45% of patients who complete therapy show MRI changes consistent with tumor progression yet they improve on continued chemotherapy with TMZ. This pseudoprogression is an important problem; clinicians armed with MRI alone wrongly conclude that standard treatment is failing in 9-45% of cases. Wrongly diagnosing tumor progression could risk entering patients into phase II trials of new agents, leading to falsely positive outcomes. Our hypothesis is that FLT PET plus MRI can distinguish between true tumor progression and pseudoprogression in patients with GBM that finish initial therapy with external beam RT plus concurrent TMZ.

自从该程序启动以来，增殖成像一直是该程序的重​​点，最初是使用[2- [11] c] - 胸苷（TDR）纳入DNA中的。稍后，我们引入了[[18] f] -flt（flt）。通过打捞途径的DNA合成速率为估计肿瘤的生长速率和对治疗的响应变化提供了一种强大的方法。简单的flt {suv}并不能可靠地表明细胞增殖。进一步的工作对于验证FLT与TDR相比测量细胞增殖的效果至关重要。我们对这两个示踪剂的应用需要通过血液采样和数学建模进行动态成像，以将示踪剂的磁通（保留）与运输分离。还值得探索更简单的方法，以基于图像的动脉输入功能和最少数量的静脉样本来获取重要参数数据，以校准输入功能并分析代谢物。 一般化：我们已经在脑肿瘤中发表了TDR和FLT的分析方法，现在将将其推广到其他肿瘤部位，直接比较TDR和FLT，以确定FLT的通量和FLT的运输是否能够准确地指示细胞增殖与TDR的措施。具体而言，我们将比较治疗前后的神经胶质瘤，白血病，肉瘤，肾脏和GL癌患者的这两个示踪剂。我们的假设是，具有适当数据分析的FLT可以与TDR一样准确，以报告肿瘤增殖和对治疗的反应。 简化：我们简化PET程序的方法将通过最少的静脉抽样评估，以鉴定标记的代谢物。我们的假设是，可以使用简化的程序来维持通量和运输估计的准确性。 是否进步？新诊断的胶质母细胞瘤的标准疗法为60 Gy RT以及并发的替莫唑胺（TMZ）化学疗法。从9％到45％的患者完成治疗的患者表明MRI变化与肿瘤进展一致，但在与TMZ的持续化学疗法方面有所改善。这种伪造是一个重要的问题。单独使用MRI的临床医生错误地得出结论认为，在9-45％的病例中，标准治疗失败了。错误地诊断肿瘤进展可能会使患者进入新药物的II期试验，从而导致错误的阳性结果。我们的假设是，FLT PET Plus MRI可以区分GBM患者的真正肿瘤进展和伪雌性，这些患者使用外束RT加上并发的TMZ结束初始治疗。