Molecular MR Imaging of the Desmoplastic Response in Pancreatic Cancer

 描述（由申请人提供）：我们建议通过使用胶原特异性磁共振成像（MRI）探头CM-101询问这些病变的促纤维增生基质，建立一种新的胰腺导管腺癌（PDAC）微环境非侵入性表征方法。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通常在转移灶出现之前不会被检测到，并且对许多传统的化疗药物不敏感，这导致了6.7%的令人沮丧的五年生存率。PDAC特别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”，其以复杂的方式影响肿瘤存活和进展。促结缔组织增生间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肿瘤的促结缔组织增生状态。我们打算通过开发一种基于I型胶原特异性对比增强的高分辨率MRI方法来表征结缔组织增生，从而满足这一需求。我们的初步数据已经确定，原型I型胶原靶向成像探针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），易于从血管外渗到肿瘤组织中。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具有与EP-3533相同的作用机制，但已进行了改进，以纳入非常稳定的大环GdDOTAGA螯合物，这是防止人体使用过程中钆解离所必需的。CM-101已使用标准固相肽和缀合偶联化学以数克规模合成，易于配制用于IV注射。CM- 101的药代动力学和胶原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确立，并证明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I期，我们将合成CM-101和突变的对照探针CM-125，并将证明类似的MR弛豫和药代动力学性质，但不存在对CM-125的胶原亲和力。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PDAC相关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推移的肿瘤渗透性和结缔组织增生（胶原蛋白含量）。我们还将使用CM-101增强MRI来监测纤维化间质对结缔组织增生抑制剂（氯沙坦）的反应。然后，我们将对接受氯沙坦和传统化疗（吉西他滨）单药治疗或联合治疗的小鼠进行成像，并确定我们是否可以使用成像来预测反应。最后，为了使临床翻译 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。

 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.