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.

谷氨酰胺解是谷氨酰胺的细胞分解代谢，是一种重要的代谢途径