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

结直肠癌(CRC)是西方世界第二大健康问题之一。 是美国癌症死亡的主要原因。虽然新的活化剂的可用性改善了 结直肠癌患者的预后、转移性疾病患者的5年总生存率仅为 13%。目前的治疗模式包括随后使用细胞毒化疗和/或 选定的目标代理。客观和准确地评估肿瘤对治疗的反应代表 肿瘤学中最大的挑战之一。及早评估治疗无效将避免 治疗对患者的毒性，并可通过允许早期治疗来提高存活率 强化、停止无效治疗或启动二线治疗。在今天的临床上 实践治疗反应评估主要基于解剖成像(MRI、CT、X光或 超声)，并侧重于肿瘤的体积和形态测量评估。不幸的是，它 治疗开始后通常需要几周到几个月的时间，然后形态才会改变 很明显。在这段时间内，无反应的患者会遭受可避免的副作用，并可能 可能受到疾病进展的影响。因此，对非侵入性的需求越来越大 分子成像生物标记物，允许早期监测治疗效果。磷脂酰乙醇胺 (Pe)仅在凋亡和死亡细胞上表达，是一种有吸引力的分子生物标志物。 检测到细胞死亡。杜拉霉素是一种天然存在的多肽抗生素，它与PE特异结合，具有 在几种动物模型中被成功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 专有的成像探针[99mTc]硬霉素，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[99mTc]杜拉霉素SPECT扫描 对于预扫描，临床医生应该能够更快地区分有反应和无反应的人 而不是用解剖学方法。该项目的具体目标包括：1)临床前验证 [99mTC]用于评价结直肠癌对最新治疗方案的反应，2)产品 HYNIC-DURAMING试剂盒符合cGMP，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第一次人类研究，以证明安全性， 生物分布和剂量学，以及5)评价[99mTc]杜拉霉素早期治疗的临床价值 结直肠癌患者的反应。 综上所述，这项研究应该表明[99mTc]杜拉霉素是否可以检测到 肿瘤治疗先于传统的成像技术，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.