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Targeting SLC7A11-induced nutrient dependency in cancer: mechanisms and preclinical translation

针对 SLC7A11 诱导的癌症营养依赖性：机制和临床前转化

基本信息

批准号：
10203888
负责人：
Boyi Gan
金额：
$ 42.59万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10203888
关键词：
Amino Acid Transporter Antineoplastic Agents Biochemical Pathway CRISPR screen Cell Death Cell Line Cell Survival Cells Cysteine Cystine Data Dependence Development Disulfides Equilibrium Exhibits Genetic Glucose Glucose Transporter Goals Homeostasis Human Immune system Impairment Link Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolism Mutation NADP Nature Normal Cell Nutrient Outcome Oxidation-Reduction Pathway interactions Pentosephosphate Pathway Pharmaceutical Preparations Pre-Clinical Model Radiation therapy Research Role Solid Neoplasm Starvation Testing Therapeutic Translations Xenograft procedure antiporter cancer cell cancer therapy clinical care inhibitor/antagonist innovation insight leukemia lung cancer cell mutant novel novel therapeutic intervention novel therapeutics nutrient metabolism overexpression patient derived xenograft model pre-clinical small molecule standard of care success targeted agent therapeutic target tumor uptake

项目摘要

Project Summary Specific genetic alterations in cancer cells may reprogram their metabolic networks and render them highly dependent on particular nutrients for survival. A mechanistic understanding of nutrient dependency in cancer cells has important implications for cancer treatment because drugs that impair nutrient metabolism may be effective for killing cancer cells that depend on specific nutrients for survival while sparing normal cells. While targeting nutrient dependency has been successful in leukemia, to date there has been limited success in targeting nutrient dependency in solid tumors. Therefore, there is a significant need to understand the mechanisms of action of anti-neoplastic agents that target nutrient dependency in cancer cells. SLC7A11 is an amino acid transporter that enables cystine uptake and its subsequent conversion to cysteine, which is critical for maintaining redox balance and cell survival. SLC7A11 is frequently overexpressed in human cancers, including KEAP1-mutant lung cancers. This application aims to determine the roles and mechanisms of SLC7A11 in regulating nutrient dependency and to therapeutically target nutrient dependency in cancers with aberrant expression of SLC7A11. Our specific aims are: Specific Aim 1: To determine the metabolic mechanisms underlying SLC7A11-induced glucose dependency in cancer cells. Specific Aim 2: To determine the therapeutic potential of inhibiting GLUTs or the PPP in treating tumors with aberrant SLC7A11 expression. The rationale for the proposed research is that studying the roles of SLC7A11 in regulating glucose dependency will not only advance our mechanistic understanding of nutrient dependency in cancer cells but also provide important insights into the development of novel therapeutic strategies to target metabolic vulnerabilities in SLC7A11- overexpressing tumors. Our proposed studies will have significant impact on both our understanding of the fundamental mechanisms of nutrient dependency and our ability to therapeutically target nutrient dependency in cancer treatment.

项目摘要癌细胞中的特定基因改变可能会重新编程它们的代谢网络，并使它们高度依靠特定的营养来生存。对癌症中营养依赖的机制认识细胞对癌症治疗具有重要意义，因为损害营养新陈代谢的药物可能有效杀死依赖特定营养物质生存的癌细胞，同时保留正常细胞。而当针对营养依赖的治疗在白血病中取得了成功，到目前为止，在以下方面的成功有限针对实体肿瘤的营养依赖。因此，有必要了解针对癌细胞中营养依赖的抗肿瘤药物的作用机制。SLC7A11是一款氨基酸转运体，能够摄取半胱氨酸并随后转化为半胱氨酸，这是至关重要的用来维持氧化还原平衡和细胞存活。SLC7A11在人类癌症中经常过表达，包括Keap1基因突变的肺癌。本申请旨在确定以下角色和机制 SLC7A11在调节癌症患者营养依赖和治疗靶向营养依赖中的作用 SLC7A11基因异常表达。我们的具体目标是：具体目标1：确定代谢机制潜在的SLC7A11诱导癌细胞对葡萄糖的依赖。具体目标2：确定治疗方法抑制Gluts或PPP在治疗SLC7A11异常表达肿瘤中的潜力。其基本原理是这项拟议的研究是，研究SLC7A11在调节葡萄糖依赖方面的作用不仅将促进我们对癌细胞中营养依赖的机制的理解，同时也提供了重要的针对SLC7A11代谢易损性的新治疗策略开发的见解- 过度表达的肿瘤。我们建议的研究将对我们对营养依赖的基本机制和我们在治疗中针对营养依赖的能力癌症治疗。