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

项目总结/摘要 该图像引导药物递送（IGDD）提案的目标是克服翻译障碍，如所述 在PAR-16-044中，创建了一种新的定量成像方法，可改善 癌症靶点，以更好地选择药物和输送，以及改善实时监测是否 药物靶点得到有效治疗。这将通过使用一种新的双探针（13 C丙酮酸和 13 C谷氨酰胺）超极化（HP）13 C代谢成像技术以区分生物学上的分歧 晚期腺癌的治疗后出现的神经内分泌前列腺癌（NEPC）， NEPC肿瘤的代谢谱，并使用代谢的实时变化来监测药物的输送 和功效。NEPC是前列腺癌的一种日益普遍的致命亚型， 雄激素阻断治疗和第二代强效雄激素通路的应用反应 抑制剂的既没有血液检查（如PSA或血清神经内分泌标志物），也没有标准成像指标 (like FDG PET）可靠地区分NEPC和腺癌，也不能量化神经内分泌的程度。 分化这项建议的科学前提是基于：（i）我们的1期临床试验的成功， 前列腺癌患者中的HP 13 C-丙酮酸盐MRI（7），（ii）市售临床 偏振器，（iii）成像转移性肿瘤的技术能力，以及（iv）强大的临床前数据 证明了HP 13 C代谢MRI在定量MYC介导的代谢失调中的价值 与神经内分泌分化相关，并测量其对治疗的反应。临床 翻译这种范式转变IGDD方法，以改善晚期前列腺患者的治疗 癌症是及时的，并且满足了新的重要的未满足的临床需求。 为了完成这一重要项目，我们组建了一支由基础科学和临床医学专家组成的优秀团队。 研究人员在临床前和临床癌症研究，HP 13 C MRI， 领先的成像和治疗临床试验：确定NEPC的分子和代谢特征 肿瘤和开发新的HP 13 C标记探针，以确定神经内分泌分化和治疗 缓解（目标1）;定义患者中转移性NEPC肿瘤的分子和代谢特征， 与HP 13 C乳酸盐-乳酸盐通量（kPL）测量值相关（目标2）;进行首次系列组合 HP 13 C-丙酮酸盐和HP 13 C-谷氨酰胺MRI用于研究鉴别NEPC和 腺癌和监测对治疗的反应（目的3）。关于NEPC生物学的新研究 启发了治疗这种疾病的新的研究方法，虽然这项建议将集中在 目前的护理治疗标准，新的定量HP 13 C代谢MRI方法在此开发， 该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 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.