Novel Hyperpolarized MR Markers of Advanced Prostate Cancer Therapy

描述(申请人提供)：这项研究旨在利用一种新型的超极化(HP)分子成像探针协同组合，研究与去势耐受前列腺癌(CRPC)的发展相关的细胞内代谢和肿瘤微环境的表型变化及其治疗的早期反应。雄激素剥夺治疗是治疗复发或转移性疾病的基石，但最终患者对雄激素剥夺失去反应，发展为致命性CRPC。随着对CRPC认识的不断深入，大量有效延缓CRPC生长的新的治疗方法被开发出来并进行了临床评价。然而，目前的生化、临床和影像生物标记物并不能可靠地预测慢性阻塞性肺疾病的发展或随后的治疗反应。HP MR是一种革命性的新MR分子成像技术，为HP 13C标记的探针提供10,000倍的信号增强，使快速、非侵入性监测多个途径特定的代谢过程成为可能。我们在前列腺癌转基因小鼠模型(TRAMP)中的强大初步数据已经证明了使用HP[1-13C]丙酮酸对前列腺癌原发和转移进行分级的潜力。该项目将首次调查HP MRIN对CPRC发展的早期评估及其对新的二线抗雄激素治疗的后续反应。在TRAMP和人体组织切片模型中，我们将进一步评估HP丙酮酸代谢，用HP探针检测灌注、间质pH和坏死，以加深我们对CPRC对肿瘤微环境变化和治疗反应的理解。为了提供建议的HP探针的个体价值和协同作用的最佳指示，我们将结合人前列腺TSCs的能力，以更好地原位反映复杂的病理、功能、代谢和雄激素敏感性，并结合TRAMP模型提供的关于肿瘤微环境的信息。除了这些关键的临床前研究外，该项目还将通过获得第一个关于CRPC患者抗雄激素治疗反应的惠普磁共振数据，扩大HP[1-13C]丙酮酸I前列腺癌患者成功的第一阶段临床试验。这项研究的长期目标是提供配套的磁共振成像生物标记物，可用于为CRPC患者量身定制治疗，并有利于未来新疗法的临床前研究和后续临床试验。因此，这些 具有里程碑意义的研究将对CRPC新疗法的开发以及HP MR的新领域产生重大影响。

DESCRIPTION (provided by applicant): This research aims to investigate phenotypic changes in intracellular metabolism and tumor micro-environment associated with the development of castrate resistant prostate cancer (CRPC) and its early response to therapy using a novel synergistic combination of hyperpolarized (HP) molecular imaging probes. Androgen deprivation therapy is the cornerstone of treatment for patients with recurrent or metastatic disease, but eventually patients stop responding to androgen deprivation and develop lethal CRPC. Advances in the understanding of CRPC have led to the development and clinical evaluation of a large number of new therapeutic approaches that effectively retard the growth of CRPC. However, current biochemical, clinical, and imaging biomarkers do not reliably predict the development of CPRC, or its subsequent response to therapy. HP MR is a revolutionary new MR molecular imaging technique providing 10,000-fold signal enhancement for HP 13C labeled probes, enabling rapid, noninvasive monitoring of multiple pathway-specific metabolic processes. Our strong preliminary data in the transgenic murine model of prostate cancer (TRAMP) have demonstrated the potential for using HP [1-13C] pyruvate to grade primary and metastatic prostate cancer. This project will investigate, for the first time, the utility of HP MRin early assessment of CPRC development and its subsequent response to a new 2nd-line anti-androgen therapy. In the TRAMP and human tissue slice models, we will further evaluate HP pyruvate metabolism, with HP probes of perfusion, interstitial pH and necrosis to advance our understanding of changes in tumor microenvironment with CPRC and therapeutic response. To provide the best indication of the individual value and synergistic role of the proposed HP probes, we will combine the ability of human prostate TSCs to better reflect the complex pathology, function, metabolism and androgen sensitivity in situ with information concerning the tumor micro-environment provided by the TRAMP model. In addition to these critical preclinical studies, this project will expand on the successful Phase 1 clinical trial of HP [1-13C] pyruvate i prostate cancer patients by obtaining the first HP MR data on response to anti- androgen therapy in CRPC patients. The long-term goal of this research is to provide companion MR imaging biomarkers that can be used to tailor treatment to individual patients with CRPC and to benefit future preclinical studies of new therapies and subsequent clinical trials. Therefore these landmark studies will greatly impact both the development of new therapeutics for CRPC as well as the new field of HP MR.