Targeted inhibition of metabolic pathways to enhance radiopharmaceutical therapy

靶向抑制代谢途径以增强放射性药物治疗

• 批准号: 10356588
• 负责人: Sangeeta Ray
• 金额: $ 19.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356588
• 关键词: Address; Adopted; Adoption; Adverse effects; Alpha Particles; Antigen Targeting; Beta Particle; Biological Assay; Blood Vessels; Cell Line; Cell Survival; Cell surface; Cells; Clear cell renal cell carcinoma; Clinical; Combined Modality Therapy; DNA Damage; DNA Repair; DNA Sequence Alteration; Data; Disease; FOLH1 gene; Functional disorder; Glutamates; Glutaminase; Glutamine; Goals; Human; Image; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Injectable; Ionizing radiation; Label; Lacrimal gland structure; Low Dose Radiation; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic Pathway; Metabolism; Minority; Modeling; Molecular; Mutation; Neoplasm Metastasis; Neuroendocrine Tumors; Nucleotides; Nutrient; Pathway interactions; Patient-Focused Outcomes; Patients; Phase I/II Clinical Trial; Process; Production; Radiation; Radiation therapy; Radioisotopes; Radiopharmaceuticals; Radiosensitization; Reaction; Reactive Oxygen Species; Reduced Glutathione; Renal carcinoma; Research; Resistance; Resistance development; Role; Salivary Glands; Solid Neoplasm; Testing; Therapeutic; Therapeutic Agents; Translating; Translations; Treatment Efficacy; Treatment Failure; Tumor Cell Invasion; angiogenesis; base; cancer care; cancer cell; castration resistant prostate cancer; cell killing; clinically significant; experience; implantation; improved; in vivo; inhibitor; neoplastic cell; neovasculature; novel; overexpression; particle; patient derived xenograft model; phase III trial; pre-clinical; prevent; prognostic indicator; radiation delivery; radioresistant; response; scaffold; small molecule; standard of care; synergism; theranostics; treatment response; tumor; tumor growth; tumor hypoxia; tumor metabolism; tumor microenvironment; uptake

Glutamine is a major nutrient involved in several aspects of cancer metabolism. Glutaminase1 (GLS1) initiates that process by converting glutamine to glutamate that is subsequently used in multiple reactions that support tumor cell survival. Accordingly, GLS1 inhibition is a promising approach to treat tumors dependent on glutamate. Here we focus on targeted inhibition of GLS1 to provide a new strategy to enhance the effect of prostate-specific membrane antigen-based radiopharmaceutical therapy (PSMA-RPT) to treat metastatic clear cell renal cell carcinoma (mRCC). mRCC is lethal, with a 5-year survival of only 12%. Although immunotherapy with checkpoint inhibitors has demonstrated improved overall survival, only a minority of patients reliably respond. PSMA displays high expression within the neovasculature of aggressive mRCC, and is a negative prognostic indicator. Because tumor neovasculature is an established target for approved therapies for mRCC, we hypothesize that PSMA-RPT can be a new and effective anti-vascular radiotherapy. Many cancer-associated mutations reprogram the metabolism of mRCC with increased glutamine utilization through GLS1. Inhibition of GLS1 reduces DNA repair in mRCC through decreased nucleotide production and reduces glutathione synthesis while independently making the tumor cells vulnerable to DNA damage. We hypothesize that inhibition of GLS1 will enhance PSMA-RPT by inducing further DNA damage to the cancer cells. Inhibition of GLS1 has not been evaluated with RPT in general, or in PSMA-RPT, specifically. The availability of clinically tested GLS1 inhibitors and PSMA-RPT renders this combined approach rapidly translatable. We discovered small-molecule PSMA targeting, particularly for imaging, and have developed the corresponding radiotherapeutic agents over many years. We recently translated an optimized 177Lu-labeled β- particle-emitting compound (PSMA-R2/L1) for treating prostate cancer. While maintaining tumor uptake, our compound showed significantly lower salivary gland uptake than existing agents in human studies, suggesting that PSMA-RPT with 225Ac-L1 will improve the therapeutic window of α-particle-based radiotherapy. We plan to evaluate 177Lu-L1 and 225Ac-L1 because of the different radiobiologic effects of the particles, including DNA damage activity in the hypoxic tumor microenvironment of mRCC. We have developed several mRCC cell lines in vitro and tumor models with variable GLS1 and PSMA levels and a patient-drived tumor model for a proof-of- concept study. Specific Aims: Aim 1. To access the efficacy of 177Lu-L1 or 225Ac-L1 in combination with a GLS1 inhibitor in vitro. Aim 2. To assess the efficacy of 177Lu-L1 or 225Ac-L1 in combination with a GLS1 inhibitor in vivo in relevant tumor models in orthotopic implantation. If successful, our research may have a near-term and significant impact on improving patient outcomes.

谷氨酰胺是一种主要的营养素，参与了癌症代谢的几个方面。谷氨酰胺酶（GLS1）启动