Development and Translation of Hyperpolarized C-13 Prostate Cancer MRI Methods

描述(申请人提供)：前列腺癌在美国是一个主要的健康问题，每年有240,000个新病例和28,000个死亡。由于使用血清前列腺特异性抗原(PSA)和扩展模板经直肠超声(TRUS)引导活检的筛查增加，前列腺癌患者被发现的时间更早，而且可能更容易治疗。不幸的是，辨证分型具有临床意义 使用目前可用的临床和影像预后数据通常不能可靠地确定由惰性疾病引起的癌症。此外，准确成像转移性前列腺癌治疗反应的能力也是一个至关重要的未得到满足的临床需求。初步数据有力地表明，使用动态核极化(DNP)的超极化13C-丙酮酸MRI具有显著改善前列腺癌临床治疗的潜力。这个生物工程合作项目的目标是开发和转化新的超极化碳-13磁共振代谢成像技术，使人类前列腺癌研究首次能够调查癌症的存在(由术后组织病理学定义)、分级和转移肿瘤的治疗反应。临床前研究和NIH支持的白皮书清楚地证明了这种强大的方法通过特定的酶途径检测癌症模型中异常代谢的潜力，并与分级和治疗反应显著相关。我们最近完成的剂量递增第一阶段安全试验证明了使用超极化[1-13C]丙酮酸不仅可以检测其在前列腺中的摄取，还可以检测其在可疑癌症区域通过LDH(在癌症中上调)转化为13C-乳酸的安全性和可行性。这项BRP中提出的研究为前列腺癌患者超极化[1-13C]丙酮酸成像的临床翻译迈出了关键的下一步。需要新的技术和患者研究来研究其临床潜力，并将这项工作扩展到第一次TME的转移性疾病部位的研究。虽然成功地证明了安全性和设计的“概念验证”，但小型第一阶段试验没有调查临床价值，并使用了基本的获取技术。拟议的生物工程研究伙伴项目需要开发、翻译和应用新的惠普13C磁共振技术，对惠普13C-丙酮酸MR解决前列腺癌原发和转移性患者管理中未满足的临床需求的能力进行史无前例的“第一人”研究。为了完成这一重要项目，我们组建了一支经验丰富的多学科研究团队，结合了MR生物工程、超极化(HP)13C研究、高级MRI数据分析、无菌药物合成、泌尿学、肿瘤学、病理学、放射学和研究治疗学等领域的广泛专业知识。研究设施和环境包括成功完成拟议的翻译BRP项目所需的DNP偏振器、多个磁共振系统和临床研究基础设施。

DESCRIPTION (provided by applicant): Prostate cancer is a major health concern in the United States with >240,000 new cases per year and >28,000 deaths. Due to increased screening using serum prostate specific antigen (PSA) and extended-template transrectal ultrasound (TRUS) guided biopsies, patients with prostate cancer are being identified at earlier and potentially more treatable stages. Unfortunately, the differentiation of clinically significant cancer from indolent disease is often not reliably determined using currently available clinical and imaging prognostic data. Also the ability to accurately image treatment response in metastatic prostate cancers is also a critically important unmet clinical need. Preliminary data strongly indicate that hyperpolarized 13C-pyruvate MRI using dynamic nuclear polarization (DNP) has the potential to dramatically improve prostate cancer clinical management. The goal of this Bioengineering Partnership project is to develop and translate new hyperpolarized carbon-13 MR metabolic imaging techniques to enable human prostate studies investigating for the first time cancer presence (defined by post-surgery histopathology), grade, and metastatic tumors with response to therapy. Preclinical studies and an NIH-supported White paper have clearly demonstrated the potential of this powerful method to detect abnormal metabolism through specific enzymatic pathways in cancer models with significant correlations to grade and treatment response. The dose-escalation Phase 1 safety trial that we recently completed demonstrated the safety and feasibility of using hyperpolarized [1-13C] pyruvate to detect not only its uptake in the prostate, but also its enzymatic conversion through LDH (up-regulated in cancer) to 13C-lactate in regions of suspected cancer. The research proposed in this BRP takes the critical next step in the clinical translation of hyperpolarized [1- 13C] pyruvate imaging of patients with prostate cancer. New techniques and patient studies are required to investigate its clinical potential and to extend this work to the study of metastatic disease sites for the first tme. While successful in demonstrating safety and "proof-of-concept" as designed, the small Phase 1 trial did not investigate clinical value and used rudimentary acquisition techniques. The proposed Bioengineering Research Partnership project is required to develop, translate, and apply new HP 13C MRI techniques for unprecedented "First-in-Man" investigations of the ability of HP 13C-pyruvate MR to address unmet clinical needs in the management of primary and metastatic prostate cancer patients. To accomplish this important project, we have assembled a highly-experienced multidisciplinary research team combining extensive expertise in MR bioengineering, hyperpolarized (HP) 13C research, advanced MRI data analysis, sterile pharmaceutical compounding, Urology, Oncology, Pathology, Radiology, and Investigational Therapeutics. The research facilities and environment includes the DNP polarizers, multiple MR systems and clinical research infrastructure required for successful completion of the proposed translational BRP project.