Theranostic for gastric cancer

胃癌的治疗诊断

• 批准号: 10699365
• 负责人: Valerie Humblet
• 金额: $ 39.59万
• 依托单位: COLLAGEN MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10699365
• 关键词: 90Y; Address; Beta Particle; Binding; Biodistribution; Blood Proteins; Cancer Etiology; Cancer Patient; Cessation of life; Clinical; Collagen; Combination Drug Therapy; Control Groups; Copper; Cyclic GMP; Cyclic Peptides; Data; Deposition; Derivation procedure; Detection; Dose; Drug Kinetics; Extracellular Matrix; Extravasation; Fibrin; Frequencies; Gastric Tissue; Histologic; Human; Image; Immunohistochemistry; Injections; Kinetics; Legal patent; Licensing; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Medical; Methods; Neoplasm Metastasis; Organ; Outcome; Patients; Peptides; Phase; Positron-Emission Tomography; Prevalence; Prognosis; Radiation therapy; Radiolabeled; Rattus; Rodent; Safety; Signal Transduction; Specificity; Stomach Neoplasms; Targeted Radiotherapy; Therapeutic Effect; Thrombus; Time; Tissue Microarray; Tissues; Toxic effect; Treatment Protocols; Treatment outcome; advanced disease; clinical translation; dosage; dosimetry; human model; image guided therapy; improved; malignant stomach neoplasm; mouse model; neoplastic cell; novel therapeutic intervention; patient derived xenograft model; patient prognosis; response biomarker; targeted treatment; theranostics; therapeutic target; tool; translational therapeutics; treatment optimization; treatment response; tumor; tumor growth; tumor microenvironment; uptake

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.

项目概要 The overarching objective of this application is to develop an image-guided therapy paradigm for 通过靶向肿瘤中的纤维蛋白改善胃癌 (GCa) 的治疗 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 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 即使采用联合化疗，生存期仍可达 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。原发性和转移性胃肿瘤 脉管系统渗漏，导致血液蛋白外渗和纤维蛋白在血液中大量沉积 细胞外基质（ECM）。鉴于纤维蛋白仅存在于肿瘤和血栓中，但不存在于健康体内 组织中，我们认为纤维蛋白可以用作治疗靶点，代表 ECM 中的一个大库，可用于 高能β粒子杀死周围的肿瘤细胞。 Collagen Medical 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，纤维蛋白 靶向正电子发射断层扫描 (PET) 可以使用铜 64 修饰肽检测患者的血栓， 但在 GCa 转移的组织中提供最小的背景 PET 信号。 我们的初步数据表明，纤维蛋白特异性探针 64Cu-CM500 可检测小鼠模型中的纤维蛋白 GCa。我们还对肽进行了修饰，以纳入高能 β 发射体 yttrium-90，用于靶向 治疗。基于这些初步数据，在这个 FastTrack 项目中，我们建议建立 使用 64Cu-CM500 PET 来识别富含纤维蛋白胃病的患者来治疗 GCa 的治疗诊断方法 肿瘤，然后用纤维蛋白靶向 90Y-CM600 β 发射放射疗法治疗它们。在第一阶段我们 将评估各种人类 GCa 组织阵列中纤维蛋白沉积的程度，以估计 GCa 中纤维蛋白的普遍性。我们还将展示我们的化合物在检测方面的特异性 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 对 GCa 患者的肿瘤进行 PET 扫描，并估计探针与肿瘤结合的时间。我们还将 证明 90Y-CM600 放射治疗在多个 GCa 小鼠模型中的疗效并优化 治疗方案。 最后，为了实现该疗法的临床转化，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，以实现 GLP 毒性、生物分布和 啮齿动物的剂量测定研究。