Theranostic for gastric cancer

项目摘要 此应用程序的总体目标是开发一种图像引导的治疗范例 通过靶向肿瘤内的纤维蛋白改善胃癌(GCA)的治疗 微环境。GCA是第五种最常见的癌症，也是癌症相关死亡的第三大原因 全世界。尽管晚期GCA的治疗取得了进展，但预后仍然很差，中位数为 即使联合化疗也能存活12-14个月。因此，新的治疗方法是 最需要改善晚期疾病患者的临床结果。 中心假设是高能β粒子放射治疗针对肿瘤中的纤维蛋白 微环境改善GCA的治疗效果。原发和转移性胃肿瘤 血管渗漏导致血液蛋白外溢和纤维蛋白在血管内大量沉积。 细胞外基质(ECM)。鉴于纤维蛋白只存在于肿瘤和血栓中，而不存在于健康人中 组织，我们假设纤维蛋白可以被用作治疗靶点，代表着ECM中一个巨大的仓库 高能的β粒子可以杀死周围的肿瘤细胞。胶原蛋白医疗公司已开发并获得专利许可 纤维蛋白特异性短环肽，并将其衍生化，用于成像和治疗。我们已经证明了纤维蛋白- 靶向正电子发射断层扫描可以检测使用铜-修饰多肽的患者的血栓， 但在GCA转移的组织中提供最小的本底PET信号。 我们的初步数据显示，纤维蛋白特异的探针64Cu-CM500在小鼠模型中检测到纤维蛋白 GCA的。我们还对多肽进行了修改，以加入高能发射体Y-90作为靶向 心理治疗。基于这个初步数据，在这个FastTrack项目中，我们建议建立 64Cu-CM500型正电子发射计算机断层显像鉴别富含纤维蛋白的胃粘膜病变治疗GCA 然后用纤维蛋白靶向的90Y-CM600β放射治疗肿瘤。在第1阶段，我们 将评估纤维蛋白在大范围人类GCA组织阵列中的沉积程度以估计 纤维蛋白在GCA中的患病率。我们还将展示我们的化合物在这两种检测中的特异性 肿瘤纤维蛋白和靶向纤维蛋白用于放射治疗。在第二阶段，我们将评估64Cu-CM500的动力学 在GCA患者的肿瘤中进行PET检查，并估计探针与肿瘤结合的时间。我们还将 证明90Y-CM600放射治疗在多种小鼠GCA模型中的疗效，并优化 治疗方案。 最后，为了使这种疗法的临床翻译成为可能，我们将在cGMP下合成CM600前体 条件，验证90Y放射性标记方法，并执行IND使GLP毒性、生物分布和 啮齿类动物的剂量学研究。

Project Summary The overarching objective of this application is to develop an image-guided therapy paradigm for improving the management of gastric cancer (GCa) by targeting fibrin in the tumor microenvironment. GCa is the fifth most common cancer and the third leading cause of cancer-related death worldwide. Despite progress in management of advanced GCa, the prognosis remains poor with a median survival of 12-14 months even with combination chemotherapy. Therefore, novel therapeutic approaches are of utmost need to improve clinical outcomes in patients with advanced disease. The central hypothesis is that high energy beta particle radiotherapy targeted to the fibrin in tumor microenvironment improves the treatment outcome of GCa. Primary and metastatic gastric tumors have leaky vasculature which results in extravasation of blood proteins and abundant deposition of fibrin in the extracellular matrix (ECM). Given that fibrin is only present in the tumors and thrombi, but not in healthy tissues, we posit that fibrin could be used as a therapeutic target, representing a large depot in the ECM for a high energy beta particle to kill surrounding tumor cells. Collagen Medical has developed and licensed patented fibrin-specific short cyclic peptides and derivatized them for imaging and therapy. We have shown that fibrin- targeted positron emission tomography (PET) can detect thrombi in patients using a copper-64 modified peptide, yet provides minimal background PET signal in tissues where GCa metastasizes. Our preliminary data shows that the fibrin-specific probe, 64Cu-CM500, detects fibrin in a mouse model of GCa. We have also modified the peptide to incorporate the high energy beta emitter yttrium-90 for targeted therapy. Building upon this preliminary data, in this FastTrack project we propose to establish a theranostic approach to treating GCa by using 64Cu-CM500 PET to identify patients with fibrin-rich gastric tumors and then treating them with fibrin-targeted 90Y-CM600 beta emitting radiotherapy. In Phase 1 we will evaluate the extent of fibrin deposition in a wide range of human GCa tissue arrays to estimate the prevalence of fibrin in GCa. We will also demonstrate the specificity of our compounds for both detecting tumor fibrin and for targeting fibrin for radiotherapy. In Phase 2 we will evaluate the kinetics of 64Cu-CM500 PET in tumors in GCa patients and estimate how long the probe remains bound to the tumor. We will also demonstrate the efficacy of 90Y-CM600 radiotherapy in multiple mouse models of GCa and optimize the treatment regimen. Lastly, to enable clinical translation of this therapeutic, we will synthesize the CM600 precursor under cGMP conditions, validate the 90Y radiolabeling method, and perform IND enabling GLP toxicity, biodistribution and dosimetry studies in rodents.