Targeted MRI contrast agents for differential diagnosis of prostate cancer

摘要 本项目的目标是开发一种安全有效的靶向MRI造影剂， 早期发现和鉴别诊断高危前列腺癌。前列腺癌是一种高度 癌症是一种异质性疾病，是美国男性癌症死亡的第二大原因。早期准确 高危前列腺癌的检测和鉴别诊断对于医生来说至关重要， 有效的干预措施，在可治疗阶段早期治疗疾病。我们打算写一部小说 一种靶向与上皮间质相关的癌蛋白的分子成像方法 转化（EMT）、癌细胞干细胞性、血管生成、增殖和转移。癌蛋白具有 在高危前列腺癌的肿瘤细胞外基质中高表达，在低级别肿瘤中低表达， 正常组织中无。癌蛋白的非侵入性高分辨率MRI为 高危前列腺癌的准确定位和鉴别诊断。的具体目标 项目是1）优化肽靶向MRI造影剂特异性的癌蛋白在高风险 前列腺癌和建立小鼠前列腺PDX模型; 2）进行临床前评估， 靶向MRI造影剂; 3）确定靶向MRI造影剂对 在动物肿瘤模型中早期检测和鉴别诊断高危前列腺癌，包括 患者源性肿瘤模型，以及铅靶向造影剂的毒性。我们已经证明 我们的靶向造影剂在高危前列腺检测和鉴别预后中的可行性 癌症动物模型多学科方法将由一个强大的研究团队应用， 分子成像、泌尿肿瘤学、病理学、癌症生物学和MRI方面的互补专业知识 凯斯西储大学和克利夫兰诊所的物理学。我们将确定一个 引导靶向造影剂启动全面的临床前和临床开发。目标 造影剂将有可能提供早期检测、定位和鉴别诊断， 高危前列腺癌它还可用于危险分层、主动监测和图像引导 前列腺癌的临床治疗。这一奋进的成功不仅限于更好的临床 这不仅有助于疾病的控制，而且还将提供特殊的经济和社会效益。

Abstract The goal of this project is to develop a safe and effective targeted MRI contrast agent for accurate early detection and differential diagnosis of high-risk prostate cancer. Prostate cancer is a highly heterogeneous disease and the second most cause of cancer death of men in the US. Early accurate detection and differential diagnosis of high-risk prostate cancer are critical for physicians to tailor efficacious interventions to treat the disease earlier at a treatable stage. We propose to develop a novel molecular imaging approach that targets an oncoprotein associated with epithelial-to-mesenchymal transition (EMT), cancer cell stemness, angiogenesis, proliferation, and metastasis. The oncoprotein has a high expression in the tumor extracellular matrix of high-risk prostate cancer, low in low grade tumor, none in normal tissues. Non-invasive high-resolution MRI of the oncoprotein holds a great promise for accurate localization and differential diagnosis of high-risk prostate cancer. The specific aims of the project are 1) to optimize peptide-targeted MRI contrast agents specific to the oncoprotein in high-risk prostate cancer and to establish mouse prostate PDX models; 2) to perform preclinical evaluation of the targeted MRI contrast agents; 3) to determine the effectiveness of the targeted MRI contrast agents for early detection and differential diagnosis of high-risk prostate cancer in animal tumor models, including patient-derived tumor models, and the toxicity of a lead targeted contrast agent. We have demonstrated the feasibility of our targeted contrast agents in detection and differential prognosis of high-risk prostate cancer in animal models. Multidisciplinary approaches will be applied by a strong research team with complementary expertise in molecular imaging, uro-oncology, pathology, cancer biology, and MRI physics from Case Western Reserve University and Cleveland Clinic in this project. We will identify a lead targeted contrast agent to initiate comprehensive preclinical and clinical development. The targeted contrast agent will have the potential to provide early detection, localization, and differential diagnosis of high-risk prostate cancer. It can also be used for risk stratification, active surveillance, and image-guide therapy of prostate cancer in clinical practice. Success in this endeavor is not limited to better clinical management of the disease, but will also provide exceptional economic and social benefit.