Early Prediction of Tumor Response to Treatment: Clinical Translation of [99mTc]-Duramycin

结直肠癌（CRC）是西方世界的主要健康问题之一， 是美国癌症死亡的主要原因。虽然新型活性剂的可用性已经改善了 对于CRC患者的预后，转移性疾病患者的5年总生存率仅为 百分之十三目前的治疗模式包括随后使用细胞毒性化疗和/或 选定的目标代理商。客观准确地评价肿瘤对治疗的反应， 肿瘤学最大的挑战之一。对治疗无效的早期评估将避免 对患者的治疗相关毒性，并可通过早期治疗改善生存率 强化治疗、停止无效治疗或开始二线治疗。在今天的临床 实际治疗反应评价主要基于解剖成像（MRI、CT、X射线或 超声），并侧重于肿瘤的体积和形态测量评估。可惜 通常在治疗开始后几周到几个月， 很明显在这段时间内，无反应的患者正在遭受可避免的副作用， 可能会导致疾病进展。因此，对非侵入性的 分子成像生物标志物，允许早期监测治疗效果。乙醇胺 (PE)，仅在凋亡和死亡细胞上表达，提供了一种有吸引力的分子生物标志物， 检测细胞死亡。持久霉素是一种天然存在的肽类抗生素，可特异性结合PE， 在几种动物模型中成功地用作细胞死亡成像的探针。 该项目的主要目标是进行0期和早期I期临床研究， 专利成像探针，[99 mTc]duramycin，以确定其安全性和检测癌症治疗的能力- 诱导细胞死亡。通过比较治疗开始后早期获得的[99 mTc]duramycin SPECT扫描， 对于治疗前扫描，临床医生应该能够更快地区分反应者和无反应者。 而不是解剖学方法。本项目的具体目标包括：1）临床前验证 [99 mTc]duramycin用于评价对CRC中最新治疗方案的反应，2）生产 符合cGMP的HYNIC-杜霉素试剂盒，3）进行GLP延长单次给药 毒理学研究，4）在健康志愿者中进行首次人体研究以显示安全性， 生物分布和剂量学; 5）评价[99 mTc]duramycin早期治疗的临床价值 CRC患者的反应。 总之，本研究应显示[99 mTc]duramycin是否可以检测 在常规成像技术之前进行肿瘤治疗，并使其能够在临床实践中使用。

Colorectal cancer (CRC) is one of the major health concerns in the western world and the second leading cause of cancer death in the USA. While the availability of novel active agents has improved the prognosis of patients with CRC, patients with metastatic disease have a 5-year overall survival rate of only 13%. The current treatment paradigm consists of the subsequent use of cytotoxic chemotherapy and/or selected targeted agents. Objective and accurate evaluation of the tumor response to therapy represents one of the biggest challenges in oncology. An early assessment of therapeutic ineffectiveness will avoid treatment related toxicity to the patient and could lead to improved survival by allowing earlier treatment intensification, discontinuation of ineffective therapy, or initiation of second-line therapy. In today's clinical practice treatment response evaluation is primarily based on anatomical imaging (MRI, CT, X-ray or ultrasound), and focuses on the volumetric and morphometric assessment of the tumor. Unfortunately, it usually takes a few weeks to months after start of the therapy before morphological changes become apparent. In that time span, non-responding patients are suffering from avoidable side-effects and can possibly be subject to disease progression. Consequently, there is a growing demand for non-invasive molecular imaging biomarkers that allow early monitoring of treatment efficacy. Phosphatidylethanolamine (PE), expressed only on apoptotic and dead cells, provides an attractive molecular biomarker for the detection of cell death. Duramycin, a naturally occurring peptide antibiotic that binds specifically to PE, has been successfully used as a probe for the imaging of cell death in several animal models. The main goals of this project are to conduct Phase 0 and early Phase I clinical studies of the proprietary imaging probe, [99mTc]duramycin, to ascertain its safety and ability to detect cancer therapy- induced cell death. By comparing a [99mTc]duramycin SPECT scan obtained early after onset of the therapy to a pretreatment scan clinicians should be able to distinguish responders versus non-responders sooner than with anatomical methods. The specific aims of this project include: 1) pre-clinical validation of [99mTc]duramycin for evaluation of response to the most novel treatment options in CRC, 2) the production of HYNIC-duramycin kits in compliance with cGMP, 3) the conduct of a GLP extended single-dose toxicology study, 4) the conduct of a first-in-human study in healthy volunteers to show safety, biodistribution and dosimetry, and 5) to evaluate the clinical value of [99mTc]duramycin for early treatment response in CRC patients. In summary, this research should show whether [99mTc]duramycin can detect the effectiveness of tumor therapy before conventional imaging techniques and enable its use in clinical practice.