Targeting Neuroendocrine Prostate Cancer Using Multi-Probe Hyperpolarized 13C MRI for Improved Treatment and Therapeutic Monitoring

项目摘要/摘要 如上所述，这种图像引导药物递送(IGDD)方案的目标是克服翻译障碍 在PAR-16-044中，创建了一种新的定量成像方法，提供了改进的 癌症靶点，以更好地选择和传递药物，以及改进对是否 药物靶点得到有效治疗。这将通过使用新型双探针(13C丙酮酸盐和 13C谷氨酰胺超极化(HP)13C代谢成像技术鉴别生物分化 晚期腺癌的新发神经内分泌前列腺癌(NEPC)的治疗 NEPC肿瘤的代谢情况，并使用代谢的实时变化来监测药物的输送 和药效。NEPC是一种日益流行的、致命的前列腺癌亚型，其发生是一种适应性 雄激素剥夺疗法和第二代雄激素途径的应用反应 抑制剂。既不是血液检查(如PSA或血清神经内分泌标记物)，也不是标准成像指标 (如FDGPET)可靠地区分NEPC和腺癌，也不能量化神经内分泌的程度 差异化。这项建议的科学前提是：(I)我们的第一阶段临床试验取得成功 前列腺癌患者Hp~(13)C-丙酮酸磁共振成像(7)，(Ii)可商业化的临床增殖 偏振器，(Iii)对转移性肿瘤成像的技术能力，以及(Iv)强大的临床前数据 幽门螺杆菌13C代谢磁共振定量检测MYC介导的代谢紊乱的价值 与神经内分泌分化相关，并测量其对治疗的反应。临床部 翻译这一范式转换的IGDD方法以改进晚期前列腺癌的治疗 癌症是及时的，满足了一个新的、重要的、尚未满足的临床需求。 为了完成这一重要项目，我们组建了一支杰出的基础科学和临床团队。 研究人员在临床前和临床癌症研究、HP 13C MRI和 领先的成像和治疗临床试验：确定NEPC的分子和代谢特征 并开发新的Hp 13C标记探针以识别神经内分泌的分化和治疗 反应(目标1)；确定患者和患者转移性NEPC肿瘤的分子和代谢特征 与HP 13C丙酮酸到乳酸通量(KPL)的测量相关(目标2)；执行有史以来首次的系列合并 Hp~(13)C-丙酮酸和Hp~(13)C-谷氨酰胺MRI对鉴别NPC和NPC的临床价值 腺癌和监测治疗反应(目标3)。关于NEPC生物学的新研究有了 鼓舞人心的治疗这种疾病的新的研究方法，尽管这项提议将集中在 目前的护理治疗标准，在此开发的新的定量HP 13C代谢磁共振方法 提案将对正在开发的各种新的靶向治疗方法具有普遍适用性 对于NEPC，包括MYC转录活性和谷氨酰胺代谢的抑制剂。

PROJECT SUMMARY / ABSTRACT The goal of this image-guided drug delivery (IGDD) proposal is to overcome the translational barrier, as stated in PAR-16-044, to create a new quantitative imaging approach providing improved characterization of the cancer target for better drug selection and delivery, as well as improving real-time monitoring of whether the drug target was effectively treated. This will be accomplished by using a novel dual-probe (13C pyruvate and 13C glutamine) hyperpolarized (HP) 13C metabolic imaging technique to discriminate biologically divergent treatment-emergent neuroendocrine prostate cancer (NEPC) from advanced adenocarcinoma based on the metabolic profile of NEPC tumors and to use real-time changes in metabolism to monitor the drug's delivery and efficacy. NEPC is an increasingly prevalent, lethal subtype of prostate cancer that arises as an adaptive response to the application of androgen deprivation therapy and second-generation potent androgen pathway inhibitors. Neither blood tests (such as PSA or serum neuroendocrine markers) nor standard imaging metrics (like FDG PET) reliably distinguish NEPC from adenocarcinoma, nor quantify the degree of neuroendocrine differentiation. The scientific premise for this proposal is based on: (i) the success of our phase 1 clinical trial of HP 13C-pyruvate MRI in prostate cancer patients (7), (ii) the proliferation of commercially available clinical polarizers, (iii) the technical capability to image metastatic tumors, and (iv) the strong pre-clinical data demonstrating the value of HP 13C metabolic MRI in quantifying the MYC-mediated metabolic deregulation associated with neuroendocrine differentiation and in measuring its response to therapy. The clinical translation of this paradigm-shifting IGDD approach to improve the treatment of men with advanced prostate cancer is timely and meets a new important unmet clinical need. To accomplish this important project, we have assembled an exceptional team of basic science and clinical investigators with complimentary expertise in pre-clinical and clinical cancer research, HP 13C MRI, and in leading imaging and therapeutic clinical trials to: define the molecular and metabolic signature of NEPC tumors and develop new HP 13C labeled probes to identify neuroendocrine differentiation and treatment response (Aim 1); define the molecular and metabolic signature of metastatic NEPC tumors in patients and correlate with HP 13C pyruvate-to-lactate flux (kPL) measurements (Aim 2); perform first-ever serial combined HP 13C-pyruvate and HP 13C-glutamine MRI to investigate clinical value for distinguishing NEPC from adenocarcinoma and monitoring response to treatment (Aim 3). New research on the biology of NEPC has inspired novel investigational approaches to treating this disease, and although this proposal will focus on current standard of care treatment, the novel quantitative HP 13C metabolic MRI approaches developed in this proposal will have general applicability for a variety of new targeted therapeutic approaches being developed for NEPC including inhibitors of MYC transcriptional activity and glutamine metabolism.