Commercialization of an MRI contrast agent for differential diagnosis of prostate cancer.

摘要 前列腺癌是一种高度异质性的疾病，是导致癌症死亡的第二大原因。 美国的男人。目前评估前列腺癌风险的方法是结合前列腺特异性抗原(PSA) 筛查和随机的前列腺活检。不幸的是，这一策略未能揭示病变的位置和 不能准确区分侵袭性和非侵袭性前列腺癌。结果, 大多数患者将接受不必要的积极治疗低风险前列腺癌，以避免 正在接受治疗。积极的治疗包括手术或放射治疗，通常会导致长期的副作用，如 如尿失禁、勃起功能障碍或肠道紧迫症。因此，非侵入性和非侵入性 准确的诊断成像技术定位和鉴别高危前列腺癌提供了一种新的 帮助医生进行风险分层和决策的工具，并使数百万患者免于患上低风险 不必要的激进治疗有患癌症的风险。 分子遗传学(FKA)的使命是将一种新的 靶向上皮间充质相关癌蛋白的分子成像方法 转移(EMT)、癌细胞干性、血管生成、增殖和转移。癌蛋白有 在高危前列腺癌的肿瘤细胞外基质中高表达，在低级别前列腺癌中低表达， 在正常组织中不存在。该项目的目标是将一种安全有效的靶向对比剂商业化 用于早期准确发现、定位和鉴别诊断高危前列腺癌的试剂 核磁共振检查。在第一阶段，我们优化并确定了一种用于临床的铅靶向mri造影剂。 翻译。该项目第一阶段的所有里程碑都已实现。该代理拥有 在高危前列腺癌而不是生长缓慢的前列腺癌中增强强大的特异性对比剂的能力 动物模型中的低风险肿瘤，并有可能可视化和区分高危前列腺癌 用核磁共振检查癌症。 此SBIR第二阶段的目标是开发造影剂的先导配方，以 执行FDA要求的EIND使能研究，并将用于临床前列腺癌成像的试剂商业化 癌症。其具体目标是1)放大靶向造影剂的合成，并开发一种 用于临床前研究和临床试验的主导产品配方；2)验证 前列腺癌在临床MRI扫描仪上的成像配方及其最低有效值的确定 剂量；3)在啮齿动物身上进行EIND药代动力学和安全性研究。无创准确 前列腺癌的检测是前列腺癌治疗中尚未得到满足的临床需求。临床试验将 一旦FDA批准了EIND，就可以立即启动。我们的成像技术的成功开发 技术有可能准确地检测、定位和诊断前列腺癌，取代 侵入性前列腺活检，提高前列腺癌临床治疗的决策能力。它还 有可能对前列腺癌进行非侵入性主动监测并及时监测疾病 进展，以及影像引导治疗。

Abstract Prostate cancer is a highly heterogeneous disease and the second most cause of cancer death of men in the US. Current methods to assess prostate cancer risk combine prostate specific antigen (PSA) screening and random prostate biopsy. Unfortunately, this strategy fails to reveal the lesion’s location and does not accurately differentiate between aggressive and non-aggressive prostate cancers. As a result, most patients will receive unnecessary active treatment for low-risk prostate cancer in order to avoid under treatment. Active treatment involves surgery or radiation, often causing long-term side effects such as urinary incontinence, erectile dysfunction, or bowel urgency. Thus, development of non-invasive and accurate diagnostic imaging technology to localize and differentiate high-risk prostate cancer offer a new tool to assist physicians in risk-stratification and decision making and to spare millions patients with low- risk cancer from unnecessary aggressive treatment. The mission of Molecular Theranostics (fka Prostate Theranostics) is to commercialize 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. The goal of this project is to commercialize a safe and effective targeted contrast agent for accurate early detection, localization, and differential diagnosis of high-risk prostate cancer with MRI. In phase I, we have optimized and identified a lead targeted MRI contrast agent for clinical translation. All of the milestones in Phase I of the project have been achieved. The agent possesses the superior ability of robust specific contrast enhancement in high-risk prostate cancer, not in slow growing low-risk tumors in animal models, and has the potential to visualize and differentiate high-risk prostate cancers with MRI. The objectives of this SBIR Phase II are to develop a lead formulation of the contrast agent, to perform FDA required eIND enabling studies, and to commercialize the agent for clinical imaging prostate cancer. The specific aims are 1) to scale up the synthesis of the targeted contrast agent and develop a lead product formulation for pre-clinical study and clinical trials; 2) to validate the effectiveness of the formulation for prostate cancer imaging on a clinical MRI scanner and to determine its minimally effective dose; 3) to perform eIND-enabling pharmacokinetics and safety studies in rodents. Non-invasive accurate detection of prostate cancer is an unmet clinical need for prostate cancer management. Clinical trials will be initiated as soon as the eIND is approved by the FDA. Successful development of our imaging technology has the potential to accurately detect, localize, and diagnose prostate cancer, replace invasive prostate biopsy, and improve decision-making in clinical management of prostate cancer. It also has the potential for non-invasive active surveillance of prostate cancer and timely monitoring of disease progression, as well as image-guided therapy.