Molecular MR Imaging of the Desmoplastic Response in Pancreatic Cancer

胰腺癌促纤维增生反应的分子 MR 成像

• 批准号: 9350264
• 负责人: Valerie Humblet
• 金额: $ 100.25万
• 依托单位: COLLAGEN MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-09 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350264
• 关键词: Address; Affinity; Animals; Biochemical; Blood Vessels; Blood flow; Cancer Etiology; Cessation of life; Chelating Agents; Chemistry; Cicatrix; Collagen; Collagen Type I; Combined Modality Therapy; Complex; Coupling; Cyclic GMP; Data; Desmoplastic; Development; Disease Progression; Dissociation; Drug Kinetics; Excretory function; Fibrosis; Gadolinium; Goals; Growth; Histology; Human; Hydroxyproline; Image; Immunotherapy; Infiltration; Injection of therapeutic agent; Kidney; Lesion; Liver; Losartan; Lung; Magnetic Resonance Imaging; Malignant neoplasm of pancreas; Measures; Methods; Modeling; Molecular; Monitor; Mus; Mutate; Myocardium; Nature; Neoplasm Metastasis; Organ Model; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Peptides; Permeability; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Property; Rattus; Reaction; Resolution; Rodent; Role; Safety; Signal Transduction; Solid; Stromal Cells; Stromal Neoplasm; Survival Rate; Technology; Therapeutic Effect; Time; Tissues; Toxic effect; Toxicology; Transgenic Mice; Transgenic Organisms; United States; Work; base; chemotherapeutic agent; chemotherapy; clinical translation; contrast enhanced; gemcitabine; histological stains; imaging modality; imaging probe; improved; inhibitor/antagonist; mortality; mouse model; non-invasive imaging; outcome prediction; phase 1 study; pre-clinical; predicting response; prevent; protocol development; prototype; public health relevance; response; targeted imaging; tool; treatment effect; treatment response; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): We propose to establish a new method for non-invasive characterization of the pancreatic ductal adenocarcinoma (PDAC) microenvironment by using the collagen-specific magnetic resonance imaging (MRI) probe CM-101 to interrogate the desmoplastic stroma of these lesions. Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the United States with over 40,000 deaths each year. PDAC is often not detected until metastases are present and is insensitive to many traditional chemotherapeutic drugs, which has led to a dismal five year survival rate of 6.7%. PDAC is especially notable for an intense fibrotic stromal response known as the "desmoplastic reaction" which influences tumor survival and progression in a complex manner. Desmoplastic stroma is characterized by up to a 3-fold increase in collagen compared with the normal pancreas. Currently, there are no effective ways to non-invasively image or monitor the desmoplastic status of PDAC tumors. We intend to address this need by developing a high resolution MRI method for characterizing desmoplasia based on specific contrast enhancement of Type I collagen. Our preliminary data has established that the prototype Type I collagen-targeted imaging probe EP- 3533 can specifically detect desmoplasia in an orthotopic syngeneic PDAC mouse model. The probe is small enough (~4000 Da) that it readily extravasates from the blood vessels into the tumor interstitium. It has 3 Gd chelates for potent MRI signal enhancement. Our development compound CM-101 shares the same mechanism of action as EP-3533 but has been refined to incorporate the exceedingly stable macrocyclic GdDOTAGA chelates, which are necessary to prevent gadolinium dissociation during human use. CM-101 has been synthesized on a multi-gram scale using standard solid phase peptide and conjugation coupling chemistries, is readily formulated for IV injection. The pharmacokinetics and collagen-targeting efficacy of CM- 101 have been established in rodent and large animal preclinical models of organ fibrosis, and demonstrate rapid distribution to the fibrotic target, fast renal excretion, and whole body elimination. In Phase I of this study, we will synthesize CM-101 and a mutated control probe CM-125 and will demonstrate similar MR relaxivity and pharmacokinetic properties but an absence of collagen affinity for CM-125. Next, we will evaluate the ability of CM-101 to specifically detect desmoplasia associated with PDAC, compared to the non-targeted probe CM-125 and the standard GdDTPA. In Phase 2, we will use CM-101 enhanced MRI to quantify tumor permeability and desmoplasia (collagen content) over time in a transgenic mouse model of PDAC. We will also use CM-101 enhanced MRI to monitor the reduction in fibrotic stroma in response to a desmoplasia inhibitor (losartan). We will then image mice undergoing monotherapy or combination therapy with losartan and traditional chemotherapy (gemcitabine) and determine if we can use imaging to predict response. Finally, to enable clinical translation of this technology, we will synthesize CM-101 under cGMP conditions and perform GLP toxicity studies in rodents.

 描述（由申请人提供）：我们建议通过使用胶原蛋白特异性磁共振成像（MRI）探针CM-101来询问这些病变的促纤维增生基质，建立一种非侵入性表征胰腺导管腺癌（PDAC）微环境的新方法。胰腺导管腺癌 (PDAC) 是美国癌症相关死亡的第四大原因，每年有超过 40,000 人死亡。 PDAC 通常在出现转移之前不会被检测到，并且对许多传统化疗药物不敏感，这导致五年生存率仅为 6.7%。 PDAC 尤其值得注意的是强烈的纤维化基质反应，称为“促纤维增生反应”，它以复杂的方式影响肿瘤的存活和进展。促纤维增生基质的特点是胶原蛋白比正常胰腺增加 3 倍。目前，没有有效的方法来非侵入性成像或监测 PDAC 肿瘤的促纤维增生状态。我们打算通过开发一种高分辨率 MRI 方法来满足这一需求，该方法基于 I 型胶原蛋白的特定对比度增强来表征结缔组织形成。我们的初步数据表明，原型 I 型胶原蛋白靶向成像探针 EP-3533 可以特异性检测原位同基因 PDAC 小鼠模型中的结缔组织增生。探针足够小（~4000 Da），很容易从血管渗入肿瘤间质。它具有 3 Gd 螯合物，可有效增强 MRI 信号。我们开发的化合物 CM-101 与 EP-3533 具有相同的作用机制，但经过改进，加入了极其稳定的大环 GdDOTAGA 螯合物，这对于防止人类使用过程中钆解离是必要的。 CM-101 已使用标准固相肽和共轭偶联化学方法以多克规模合成，很容易配制用于静脉注射。 CM-101 的药代动力学和胶原蛋白靶向功效已在啮齿动物和大型动物器官纤维化临床前模型中建立，并证明其可快速分布至纤维化靶点、快速肾脏排泄和全身消除。在本研究的第一阶段，我们将合成 CM-101 和突变的对照探针 CM-125，并将展示类似的 MR 弛豫性和药代动力学特性，但不存在对 CM-125 的胶原蛋白亲和力。接下来，我们将评估 CM-101 与非靶向探针 CM-125 和标准 GdDTPA 相比特异性检测与 PDAC 相关的结缔组织增生的能力。在第 2 阶段，我们将使用 CM-101 增强 MRI 来量化 PDAC 转基因小鼠模型中随时间变化的肿瘤渗透性和结缔组织形成（胶原含量）。我们还将使用 CM-101 增强 MRI 来监测纤维化基质对结缔组织增生抑制剂（洛沙坦）的反应减少情况。然后，我们将对接受氯沙坦和传统化疗（吉西他滨）单一疗法或联合疗法的小鼠进行成像，并确定是否可以使用成像来预测反应。最后，为了实现临床转化 这项技术，我们将在cGMP条件下合成CM-101，并在啮齿动物中进行GLP毒性研究。