Molecular MR Imaging of the Desmoplastic Response in Pancreatic Cancer

 描述(申请人提供)：我们建议建立一种新的方法，通过使用胶原特异性磁共振成像(MRI)探针CM-101来询问这些病变的促结缔组织间质，来非侵入性地表征胰腺导管腺癌(PDAC)的微环境。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4万人死亡。PDAC通常直到出现转移才被发现，并且对许多传统的化疗药物不敏感，这导致了令人沮丧的6.7%的五年生存率。PDAC尤其值得注意的是一种强烈的纤维间质反应，称为“促结缔组织反应”，它以一种复杂的方式影响肿瘤的生存和进展。促结缔组织增生性间质的特点是，与正常胰腺相比，胶原蛋白增加了3倍。目前，尚无有效的方法对PDAC肿瘤进行非侵入性成像或监测其促结缔组织生长状态。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，以满足这一需求。我们的初步数据已经证实，I型胶原靶向成像探针EP-3533原型可以特异性地检测同种异体原位PDAC小鼠模型中的促结缔组织增生。探针足够小(~4000Da)，很容易从血管渗入肿瘤间质。它有3个Gd络合物，可以有效地增强MRI信号。我们开发的化合物CM-101与EP-3533具有相同的作用机理，但经过改进，加入了极其稳定的大环GdDOTAGA螯合物，这是防止人类使用过程中Gd解离所必需的。CM-101是用标准固相肽和偶联化学反应在多克规模上合成的，很容易配制成静脉注射用。CM-101的药代动力学和胶原靶向效应已在啮齿动物和大动物器官纤维化的临床前模型中建立，并显示出快速分布到纤维化靶点，快速的肾脏排泄和全身消除。在这项研究的第一阶段，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松弛和药代动力学特性，但缺乏对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，特异性检测与PDAC相关的促结缔组织增生症的能力。在第二阶段，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促结缔组织增生(胶原含量)。我们还将使用CM-101增强MRI来监测纤维间质对促结缔组织增生抑制剂(氯沙坦)的反应减少。然后，我们将对正在接受氯沙坦和传统化疗(吉西他滨)单一治疗或联合治疗的小鼠进行成像，并确定是否可以使用成像来预测反应。最后，使临床翻译成为可能 在这项技术的基础上，我们将在cGMP条件下合成CM-101，并进行GLP对啮齿动物的毒性研究。

 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.