Theranostic for gastric cancer

项目摘要 本申请的首要目标是开发一种图像引导治疗范例， 通过靶向肿瘤中的纤维蛋白来改善胃癌（GCa）的管理 微环境GCa是第五大常见癌症，也是癌症相关死亡的第三大原因 国际吧尽管晚期GCa的治疗取得了进展，但预后仍然很差， 即使联合化疗，生存期也为12 - 14个月。因此，新的治疗方法是 因此，我们迫切需要改善晚期疾病患者的临床结局。 其中心假设是高能β粒子放射治疗靶向于肿瘤内的纤维蛋白 微环境改善GCa的治疗效果。原发性和转移性胃肿瘤 血管渗漏，导致血液蛋白外渗和纤维蛋白在血管中大量沉积。 细胞外基质（ECM）。鉴于纤维蛋白仅存在于肿瘤和血栓中，而不存在于健康的组织中， 组织，我们认为纤维蛋白可以用作治疗靶点，代表ECM中的一个大仓库， 高能β粒子杀死周围的肿瘤细胞。胶原蛋白医疗已开发和授权专利 纤维蛋白特异性短环肽，并将其衍生化用于成像和治疗。我们已经证明纤维蛋白- 靶向正电子发射断层摄影术（PET）可以使用铜-64修饰的肽检测患者中的血栓， 还在GCa转移的组织中提供最小的背景PET信号。 我们的初步数据显示，纤维蛋白特异性探针64Cu-CM500在小鼠模型中检测到纤维蛋白 的GCA。我们还对肽进行了修饰，使其与高能β发射体钇-90结合， 疗法在此初步数据的基础上，在此FastTrack项目中，我们建议建立 通过使用64Cu-CM500 PET来确定富含纤维蛋白的胃粘膜病变患者的治疗诊断方法 肿瘤，然后用纤维蛋白靶向的90Y-CM600 β发射放射疗法治疗它们。在第一阶段，我们 将评估大范围人类GCa组织阵列中纤维蛋白沉积的程度， GCa中纤维蛋白的患病率。我们还将证明我们的化合物的特异性， 肿瘤纤维蛋白和用于放射治疗的靶向纤维蛋白。在第2阶段，我们将评估64Cu-CM500的动力学 GCa患者肿瘤中的PET，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GCa小鼠模型中的疗效，并优化 治疗方案。 最后，为了使这种治疗剂能够临床转化，我们将在cGMP下合成CM 600前体 条件下，验证90 Y放射性标记方法，并进行IND，使GLP毒性、生物分布和 啮齿动物的剂量测定研究。

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.