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

使用多探头超极化 13C MRI 靶向神经内分泌前列腺癌以改善治疗和治疗监测

• 批准号: 9925733
• 负责人: Rahul Aggarwal
• 金额: $ 65.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925733
• 关键词: Acetates; Adenocarcinoma; Aftercare; Alanine; Androgens; Basic Science; Biological; Biological Markers; Biology; Biopsy; Blood Tests; Cancer Patient; Clinical; Clinical Data; Clinical Investigator; Clinical Management; Clinical Trials; Detection; Development; Disease; Dreams; Drug Delivery Systems; Drug Monitoring; Drug Targeting; Generations; Genetic Transcription; Genomics; Glutamates; Glutaminase; Glutamine; Glycolysis; Goals; Histologic; Histology; Image; Imaging Techniques; Investigation; Label; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Liver; Modality; Molecular; Monitor; Neoplasm Metastasis; Neurosecretory Systems; Nodal; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase I Clinical Trials; Platinum; Prediction of Response to Therapy; Primary Neoplasm; Process; Protocols documentation; Pyruvate; Research; Research Personnel; Resistance; Serum; Signal Transduction; Therapeutic; Therapeutic Clinical Trial; Time; Treatment Protocols; Up-Regulation; X-Ray Computed Tomography; abiraterone; advanced prostate cancer; aerobic glycolysis; androgen deprivation therapy; anticancer research; base; cancer genomics; castration resistant prostate cancer; chemotherapy; clinical development; clinical imaging; clinical translation; cohort; design; disorder subtype; fluorodeoxyglucose positron emission tomography; genomic signature; image guided; image-guided drug delivery; imaging approach; imaging modality; improved; improved outcome; individual patient; inhibitor/antagonist; lipid metabolism; mRNA Expression; men; metabolic imaging; metabolic profile; metabolomics; neuroendocrine differentiation; new therapeutic target; non-invasive imaging; novel; novel strategies; personalized care; pre-clinical; quantitative imaging; real time monitoring; response; response biomarker; small molecule; standard of care; success; time use; transgenic adenocarcinoma of mouse prostate; treatment response; tumor; tumor heterogeneity

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.

项目摘要 /摘要 如前所述 在PAR-16-044中，创建一种新的定量成像方法，提供了改进的表征 癌症的靶向更好的药物选择和分娩，以及改善对是否是否 有效治疗药物靶标。这将通过使用新颖的双探针（13c丙酮酸和 13c谷氨酰胺）超极化（HP）13C代谢成像技术以区分生物学上的不同 基于晚期腺癌的治疗源性神经内分泌前列腺癌（NEPC） NEPC肿瘤的代谢概况并利用代谢的实时变化来监测药物的递送 和功效。 NEPC是一种越来越普遍的致命亚型前列腺癌，作为一种自适应 对雄激素剥夺疗法的应用和第二代雄激素途径的响应 抑制剂。既没有血液检查（例如PSA或血清神经内分泌标记）也不是标准成像指标 （例如FDG PET）可靠地区分NEPC和腺癌，也可以量化神经内分泌的程度 分化。该提案的科学前提是基于：（i）我们的第一阶段临床试验的成功 前列腺癌患者中的HP 13C - 丙酮酸MRI（7），（ii）市售临床的增殖 极化器，（iii）成像转移性肿瘤的技术能力，以及（iv）强术前数据 证明HP 13C代谢MRI的值在量化MYC介导的代谢失调中 与神经内分泌分化以及测量其对治疗的反应有关。临床 这种范式转移的IGDD方法的翻译，以改善先进前列腺男性的治疗 癌症是及时的，满足了新的重要未满足的临床需求。 为了完成这个重要的项目，我们组建了一个杰出的基础科学和临床团队 具有临床前和临床癌症研究中免费专业知识的研究人员，HP 13C MRI，以及 领先的成像和治疗临床试验：定义NEPC的分子和代谢特征 肿瘤并开发新的HP 13C标记为探针，以鉴定神经内分泌分化和治疗 响应（目标1）；定义患者转移性NEPC肿瘤的分子和代谢特征 与HP 13C丙酮酸到乳酸通量（KPL）测量（AIM 2）相关；执行有史以来第一个串行组合 HP 13C-丙酮酸和HP 13C-谷氨酰胺MRI，以研究区分NEPC的临床价值 腺癌和对治疗的监测反应（AIM 3）。关于NEPC生物学的新研究 激发了治疗这种疾病的新型研究方法，尽管该提议将重点放在 当前的护理标准，新型的定量HP 13C代谢MRI方法在此中开发了 提案将对开发各种新的目标治疗方法具有一般适用性 对于NEPC，包括MYC转录活性和谷氨酰胺代谢的抑制剂。