PET Imaging of Glutamine Metabolism and Glutamate Transport to Guide Metabolically Targeted Therapy in Triple-Negative Breast Cancer

谷氨酰胺代谢和谷氨酸转运的 PET 成像指导三阴性乳腺癌的代谢靶向治疗

• 批准号: 10624784
• 负责人: DAVID A. MANKOFF
• 金额: $ 51.71万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-19 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624784
• 关键词: Amino Acids; Anabolism; Animal Model; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Model; Catabolism; Cell membrane; Cells; Cisplatin; Citric Acid Cycle; Clinic; Clinical Markers; Clinical Trials; Consumption; Data; Dependence; Enzymes; Exposure to; Extracellular Fluid; FDA approved; Glutamate Transporter; Glutamates; Glutamic Acid; Glutaminase; Glutamine; Glutathione; Growth; Homeostasis; Human; Imaging Device; Immunotherapy; Intervention; Kinetics; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methods; Mitochondria; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Paclitaxel; Pathway interactions; Patient Selection; Patient imaging; Patient-derived xenograft models of breast cancer; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Play; Positron-Emission Tomography; Pre-Clinical Model; Production; Reactive Oxygen Species; Reporting; Resistance; Role; Testing; Therapeutic; Toxic effect; Tracer; Translating; Work; Xenograft Model; alpha ketoglutarate; analog; anticancer research; antiporter; biomarker performance; biomarker validation; cancer cell; cancer clinical trial; cell growth; chemotherapy; genetic signature; imaging agent; imaging biomarker; imaging modality; inhibitor; malignant breast neoplasm; patient derived xenograft model; personalized medicine; pharmacodynamic biomarker; pre-clinical; predicting response; predictive marker; preservation; quantitative imaging; rapid growth; refractory cancer; response; targeted treatment; therapy design; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth

Glutaminolysis, the cellular catabolism of glutamine, is an important metabolic pathway for aggressive and treatment-resistant cancers, including many triple-negative breast cancers (TNBCs). It is well accepted that glutamate produced from glutamine by mitochondrial glutaminase (GLS) fuels the TAC cycle, which provides energy and precursors for biosynthesis. Emerging data have revealed a less recognized but important contribution of glutaminolysis in mediating oxidative stress introduced internally by active growth of aggressive cancer cells and externally by treatments including chemotherapy and immunotherapy. Targeting inhibitors of GLS to block glutaminolysis is a therapeutic strategy that has been tested in clinical trials of breast and other cancers with acceptable toxicity, but limited efficacy, owing in good part to a lack of clinical markers to guide patient selection and assess target impact. Preliminary data from our lab have shown that dual targeting of GLS and the plasma membrane glutamate transporter, xCT (SLC7A11), resulted in dramatic sensitization of resistant TNBC to chemotherapy. We propose three aims based upon an overall theme to develop a kinetic framework for non-metabolized amino acid analog PET tracers to measure cellular pool sizes as an indicator of catabolism and cellular transport. Specifically, we will (1) validate quantitative markers for cellular glutamine pool size from dynamic [18F]fluciclovine PET; (2) develop and validate markers for cytosolic glutamate pool size and transport using 4-(3-[18F]fluoropropyl)-L- glutamic acid ([18F]FSPG) PET, and (3) determine the utility of combined [18F]fluciclovine and [18F]FSPG PET for predicting and measuring response to dual-targeted treatment designed to sensitize TNBC to chemotherapy. As part of this work, we will address mechanistic questions regarding cytosolic glutamate transport from mitochondrial pools and to/from extracellular fluid to guide the interpretation of PET tracer kinetics. We will also test approaches to target TNBC metabolic vulnerabilities, specifically the dependence glutamine metabolism and glutamate transport, guided by the PET methods we develop and validate in our pre-clinical TNBC models. The proposed work will lead to a deeper understanding of the mutual engagement between glutaminolysis and redox homeostasis of cancer cells and will yield quantitative imaging methodologies ready to translate to the clinic.

谷氨酰胺分解，即谷氨酰胺的细胞分解代谢，是一种重要的代谢途径 用于侵袭性和难治性癌症，包括许多三阴性乳腺癌 癌症（TNBC）。人们普遍认为，谷氨酰胺通过以下方式产生谷氨酸： 线粒体谷氨酰胺酶 (GLS) 为 TAC 循环提供燃料，为 TAC 循环提供能量和 生物合成的前体。新出现的数据揭示了一个不太被认可但很重要的问题 谷氨酰胺分解在介导活性物质内部引入的氧化应激中的贡献 侵袭性癌细胞的生长以及通过包括化疗在内的外部治疗 和免疫疗法。靶向 GLS 抑制剂来阻断谷氨酰胺分解是一种治疗方法 该策略已在乳腺癌和其他癌症的临床试验中经过测试，具有可接受的效果 毒性，但疗效有限，很大程度上是由于缺乏指导患者的临床标志物 选择并评估目标影响。我们实验室的初步数据表明，双 靶向 GLS 和质膜谷氨酸转运蛋白 xCT (SLC7A11)， 导致耐药 TNBC 对化疗的显着敏感性。我们提出三个 目标基于总体主题，为非代谢性药物开发动力学框架 氨基酸类似物 PET 示踪剂，用于测量细胞池大小作为指标 分解代谢和细胞运输。具体来说，我们将 (1) 验证定量标记 来自动态 [18F]fluciclovine PET 的细胞谷氨酰胺库大小； (2) 开发和验证 使用 4-(3-[18F]氟丙基)-L- 标记细胞质谷氨酸池大小和运输 谷氨酸 ([18F]FSPG) PET，以及 (3) 确定组合 [18F]氟西洛文的效用 和 [18F]FSPG PET 用于预测和测量双靶向治疗的反应 旨在提高 TNBC 对化疗的敏感性。作为这项工作的一部分，我们将解决 有关线粒体池胞质谷氨酸转运的机制问题 以及与细胞外液的相互作用，以指导 PET 示踪动力学的解释。我们将 还测试了针对 TNBC 代谢脆弱性的方法，特别是 依赖谷氨酰胺代谢和谷氨酸转运，以 PET 方法为指导 我们在临床前 TNBC 模型中开发和验证。拟议的工作将导致 更深入地了解谷氨酰胺分解和氧化还原之间的相互作用 癌细胞的稳态，并将产生定量成像方法 翻译到诊所。