Targeted inhibition of metabolic pathways to enhance radiopharmaceutical therapy

谷氨酰胺是参与癌症代谢的几个方面的主要营养素。谷氨酰胺酶1（GLS 1）启动 该过程通过将谷氨酰胺转化为谷氨酸盐，随后用于多个反应， 肿瘤细胞存活。因此，GLS 1抑制是治疗依赖于谷氨酸的肿瘤的有前景的方法。 在这里，我们专注于靶向抑制GLS 1，以提供一种新的策略，以增强前列腺特异性 基于膜抗原的放射性药物疗法（PSMA-RPT）治疗转移性透明细胞肾细胞癌 癌（mRCC）。mRCC是致命的，5年生存率仅为12%。虽然检查点免疫疗法 尽管抑制剂已经证明改善了总体生存率，但只有少数患者可靠地应答。PSMA 在侵袭性mRCC的新生血管中显示高表达，并且是阴性预后指标。 由于肿瘤新生血管是mRCC获批治疗的既定靶点，我们假设， PSMA-RPT是一种新的有效的抗血管放射治疗方法。 许多癌症相关突变重新编程mRCC代谢，增加谷氨酰胺利用 通过GLS 1。GLS 1的抑制通过减少核苷酸产生减少mRCC中的DNA修复， 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。我们 假设GLS 1抑制将通过诱导对癌症的进一步DNA损伤来增强PSMA-RPT 细胞一般情况下，尚未使用RPT或PSMA-RPT评价GLS 1的抑制作用。的 临床测试的GLS 1抑制剂和PSMA-RPT的可用性使得这种组合方法快速 可翻译的我们发现了小分子PSMA靶向，特别是用于成像，并开发了 多年来一直使用相应的放射性物质。我们最近翻译了一个优化的177 Lu标记的β- 用于治疗前列腺癌的粒子发射化合物（PSMA-R2/L1）。在维持肿瘤摄取的同时， 在人体研究中，化合物显示出比现有药物显著更低的唾液腺摄取，表明 PSMA-RPT与225 Ac-L1联合应用可提高α粒子放射治疗的治疗窗。我们计划 评价177 Lu-L1和225 Ac-L1，因为粒子（包括DNA）的放射生物学效应不同 mRCC的缺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 体外和具有可变GLS 1和PSMA水平的肿瘤模型以及患者驱动的肿瘤模型， 概念研究具体目标：目标1。评估177 Lu-L1或225 Ac-L1与GLS 1联合使用的疗效 体外抑制剂。目标2.评估177 Lu-L1或225 Ac-L1与GLS 1抑制剂组合的体内疗效 在原位植入的相关肿瘤模型中。如果成功，我们的研究可能会有一个短期和 对改善患者预后有显著影响。

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.