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

描述（由申请人提供）：前列腺癌是美国的主要健康问题，每年有> 240，000例新发病例和> 28，000例死亡。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，前列腺癌患者在更早和可能更可治疗的阶段被发现。不幸的是，临床上显著的 使用目前可用的临床和成像预后数据，常常不能可靠地确定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满足的临床需求。初步数据强烈表明，超极化13 C-丙酮酸MRI使用动态核极化（DNP）有可能显着改善前列腺癌的临床管理。这个生物工程合作项目的目标是开发和翻译新的超极化碳-13 MR代谢成像技术，使人类前列腺研究首次调查癌症的存在（由手术后组织病理学定义），等级和转移性肿瘤与治疗反应。临床前研究和NIH支持的白色论文已经清楚地证明了这种强大的方法通过癌症模型中的特定酶途径检测异常代谢的潜力，与分级和治疗反应显著相关。我们最近完成的剂量递增I期安全性试验证明了使用超极化[1- 13 C]丙酮酸盐不仅检测其在前列腺中的摄取，而且还检测其在疑似癌症区域通过LDH（在癌症中上调）酶促转化为13 C-乳酸盐的安全性和可行性。本BRP中提出的研究在前列腺癌患者超极化[1- 13 C]丙酮酸盐成像的临床转化中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1期试验没有研究临床价值，并使用了基本的采集技术。拟议的生物工程研究伙伴关系项目需要开发、翻译和应用新的HP 13 C MRI技术，以进行前所未有的“首次人体”研究，研究HP 13 C-丙酮酸盐MR的能力，以解决原发性和转移性前列腺癌患者管理中未满足的临床需求。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）13 C研究，先进的MRI数据分析，无菌药物配制，泌尿科，肿瘤科，病理学，放射学和研究治疗学的广泛专业知识。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MR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.