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.

谷氨酰胺是参与癌症代谢的多个方面的主要营养素。谷氨酰胺1（GLS1）启动 通过将谷氨酰胺转化为谷氨酸，该过程随后在支持的多种反应中使用 肿瘤细胞存活。根据以下内容，GLS1抑制是治疗依赖谷氨酸的肿瘤的有前途方法。 在这里，我们专注于针对GLS1的有针对性抑制，以提供一种新的策略来增强前列腺特异性的影响 基于膜抗原的放射性药物治疗（PSMA-RPT）来治疗转移性透明细胞肾细胞 癌（MRCC）。 MRCC是致命的，只有5年的生存率为12％。虽然具有检查点的免疫疗法 抑制剂表明总体生存率提高了，只有少数患者可靠地反应。 PSMA 在侵略性MRCC的新生血管内显示高表达，是一个负预后指标。 因为肿瘤新生血管是MRCC批准疗法的既定靶标，所以我们假设 PSMA-RPT可以是一种新的有效的抗血管放射疗法。 许多与癌症相关的突变重编程了MRCC的代谢，并增加了谷氨酰胺利用率 通过GLS1。通过降低核苷酸的产生和 减少谷胱甘肽的合成，同时独立地使肿瘤细胞容易受到DNA损伤的影响。我们 假设抑制GLS1将通过诱导癌症的进一步DNA损伤来增强PSMA-RPT 细胞。尚未使用RPT或PSMA-RPT中的RPT评估GLS1的抑制作用。这 临床测试的GLS1抑制剂和PSMA-RPT的可用性迅速迅速 可翻译。我们发现了小分子PSMA靶向，特别是用于成像，并开发了 多年来相应的放射治疗剂。我们最近翻译了优化的177lu标记的β- 用于治疗前列腺癌的颗粒发射化合物（PSMA-R2/L1）。在维持肿瘤吸收的同时，我们 在人类研究中，与现有药物相比，唾液腺吸收的化合物明显低得多，这表明 使用225AC-L1的PSMA-RPT将改善基于α粒子的放射疗法的治疗窗口。我们计划 评估177LU-L1和225AC-L1，因为颗粒的放射生物学效应不同，包括DNA MRCC低氧肿瘤微环境中的损伤活性。我们已经开发了几种MRCC细胞系 具有可变GLS1和PSMA水平的体外和肿瘤模型以及用于证明证明的患者驱动肿瘤模型 概念研究。具体目的：目标1。访问177LU-L1或225AC-L1的效率与GLS1结合 体外抑制剂。目标2。评估177LU-L1或225AC-L1与GLS1抑制剂在体内的效率 在原位植入中相关的肿瘤模型中。如果成功的话，我们的研究可能会有近期和 对改善患者预后的重大影响。