Novel Hyperpolarized MR Markers of Advanced Prostate Cancer Therapy

描述（由申请人提供）：本研究旨在研究与去势抵抗性前列腺癌（CRPC）发展相关的细胞内代谢和肿瘤微环境的表型变化及其对使用超极化（HP）分子成像探针的新型协同组合治疗的早期反应。雄激素剥夺治疗是复发性或转移性疾病患者治疗的基础，但最终患者停止对雄激素剥夺的反应并发展为致命的CRPC。对CRPC认识的进步导致了大量有效延缓CRPC生长的新治疗方法的开发和临床评价。然而，目前的生物化学、临床和成像生物标志物不能可靠地预测CPRC的发展或其随后对治疗的反应。HP MR是一种革命性的新型MR分子成像技术，可为HP 13 C标记探针提供10，000倍的信号增强，从而实现对多途径特定代谢过程的快速无创监测。我们在前列腺癌转基因小鼠模型（TRAMP）中的强有力的初步数据已经证明了使用HP [1- 13 C]丙酮酸盐对原发性和转移性前列腺癌进行分级的潜力。该项目将首次研究HP MR在早期评估CPRC发展及其对新的二线抗雄激素治疗的反应中的效用。在TRAMP和人体组织切片模型中，我们将使用灌注、间质pH和坏死的HP探针进一步评估HP丙酮酸代谢，以促进我们对肿瘤微环境变化与CPRC和治疗反应的理解。为了提供所提出的HP探针的个体价值和协同作用的最佳指示，我们将联合收割机将人前列腺TSC的能力与TRAMP模型提供的关于肿瘤微环境的信息结合，以更好地原位反映复杂的病理、功能、代谢和雄激素敏感性。除了这些关键的临床前研究外，该项目还将通过获得CRPC患者对抗雄激素治疗反应的首个HP MR数据，扩展HP [1- 13 C]丙酮酸盐在前列腺癌患者中成功的I期临床试验。这项研究的长期目标是提供伴随的MR成像生物标志物，可用于为CRPC患者个体定制治疗，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极大地影响CRPC新疗法的开发以及HP MR的新领域。 公共卫生相关性：本项目旨在应用超极化13 C MR，一种新的分子成像技术，以解决对新的生物标志物的重要临床需求，以检测去势抵抗性前列腺癌（CRPC）的早期发展及其对治疗的反应，以提高利用抗雄激素治疗晚期疾病患者的新策略的选择和有效性。

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. PUBLIC HEALTH RELEVANCE: This project aims to apply hyperpolarized 13C MR, a new molecular imaging technique, to address the important clinical need for new biomarkers to detect the early development of castrate resistant prostate cancer (CRPC) and its response to therapy in order to enhance the selection and effectiveness of new strategies that utilize anti-androgens in the treatment of patients with advanced disease.