Targeting Glutamine Uptake via ASCT2 Inhibition in MYCN-amplified Neuroblastomas

通过抑制 MYCN 扩增的神经母细胞瘤中的 ASCT2 来靶向谷氨酰胺的摄取

• 批准号: 10543663
• 负责人: Eric James Rellinger
• 金额: $ 31.12万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543663
• 关键词: Targeting; Glutamine; Uptake; via; ASCT2

Neuroblastoma (NB) is the most common extracranial solid tumor in children. MYCN-amplification is present in ~25% of NBs and nearly half of all high-risk NBs. N-MYC is a proto-oncogene that drives cancer cell growth, angiogenesis, and metabolism. Aberrant glutamine metabolism is a hallmark of MYC-driven cancers. N-MYC enhances expression of the glutamine transporter, ASCT2. ASCT2 has been shown to be critical for MYCN-amplified NB cell survival in vitro and in subcutaneous xenograft formation in vivo. Our central hypothesis is that aberrant glutamine uptake via ASCT2 is critical for MYCN-amplified NB primary tumor growth and metastasis. We will define the critical role of ASCT2 in NB utilizing CRISPR-Cas9 knockout and V-9302, a small molecule ASCT2 inhibitor, in 3-D organoid and patient-derived orthotopic xenograft (PDOX) models of MYCN-amplified NB. Stable-isotope resolved metabolomics will be used to define aberrant metabolic pathways activated to sustain NB survival in the presence of ASCT2 blockade. We will also seek to define metabolic vulnerabilities uncovered by ASCT2 inhibition utilizing an unbiased CRISPR-Cas9 lineage dropout screen to assess for dual synthetic lethality in MYCN-amplified NB cells.

神经母细胞瘤（NB）是儿童颅外最常见的实体瘤。MYCN扩增存在于约25%的NB和近一半的高风险NB中。N-MYC是驱动癌细胞生长、血管生成和代谢的原癌基因。谷氨酰胺代谢异常是MYC驱动的癌症的标志。N-MYC增强谷氨酰胺转运蛋白ASCT 2的表达。ASCT 2已被证明对体外MYCN扩增的NB细胞存活和体内皮下异种移植物形成至关重要。我们的中心假设是通过ASCT 2的异常谷氨酰胺摄取对于MYCN扩增的NB原发性肿瘤生长和转移至关重要。我们将利用CRISPR-Cas9敲除和V-9302（一种小分子ASCT 2抑制剂）在MYCN扩增的NB的3-D类器官和患者来源的原位异种移植（PDOX）模型中定义ASCT 2在NB中的关键作用。稳定同位素分辨代谢组学将用于定义在ASCT 2阻断存在下激活以维持NB存活的异常代谢途径。我们还将寻求利用无偏倚的CRISPR-Cas9谱系缺失筛选来定义ASCT 2抑制所揭示的代谢脆弱性，以评估MYCN扩增的NB细胞中的双重合成致死性。