Investigating and targeting metabolic vulnerabilities of MYC-driven small cell lung cancer
研究和靶向 MYC 驱动的小细胞肺癌的代谢脆弱性
基本信息
- 批准号:10748278
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:ASCL1 geneAcuteAnabolismArginineArginine deiminaseAspartateBETA2 proteinCancer BiologyCancer ModelCarbonChIP-seqClinicClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyComputer AnalysisConsumptionDataData AnalysesData SetDependenceDevelopmentDiseaseDisease modelEnvironmentEnzymesFamily memberFolic Acid AntagonistsGenesGenetic TranscriptionGenetically Engineered MouseGleanGoalsHealthHumanHuntsman Cancer Institute at the University of UtahIn VitroIsotopesKnowledgeLung Neuroendocrine NeoplasmMYCL1 geneMYCN geneMalignant NeoplasmsMalignant neoplasm of lungMediatingMetabolicMetabolismMissionModelingNeoplasm MetastasisNeuroendocrine TumorsNucleotide BiosynthesisOncogenicPatientsPharmaceutical PreparationsPhysiologicalPlatinumPlayProcessRegulator GenesResearchResistanceResistance developmentResourcesRoleSecondary toSerineSpecific qualifier valueStarvationStressSystemTestingTherapeuticTimeTrainingUnited States National Institutes of Healthactivating transcription factoractivating transcription factor 4argininosuccinate synthasebase editingcancer subtypeschemotherapychromatin immunoprecipitationdeprivationdesensitizationeffective therapyexperimental studygene synthesishuman modelimprovedin vivoinhibitorlung cancer cellmetabolomicsmolecular subtypesmouse modelnovelnucleotide metabolismoverexpressionpreclinical studypreclinical trialpreventprogramsrapid growthresistance mechanismresponsesingle-cell RNA sequencingsmall cell lung carcinomastandard of caretargeted treatmenttherapeutically effectivetherapy resistanttranscription factortranscriptomicstreatment strategytumortumor metabolismurea cycle
项目摘要
PROJECT ABSTRACT
Small cell lung cancer (SCLC) is a fatal neuroendocrine lung tumor that is challenging to treat due to
early metastasis, rapid growth, and a lack of easily targetable driver alterations. For the last ~40 years, SCLC
has been treated primarily as a single disease in the clinic with combination, platinum-based chemotherapy that
offers a median survival of only ~10-12 months. It is imperative to better understand SCLC biology to enable
development of novel treatment strategies that effectively prolong patient survival. SCLC tumors amplify or
overexpress one oncogenic MYC family member: MYC, MYCL, or MYCN. MYC-high SCLCs are metabolically
distinct from MYC-low, and have specific and targetable metabolic vulnerabilities. The most effective therapeutic
strategy for treatment of MYC-high SCLCs in preclinical trials is deprivation of circulating arginine by pegylated
arginine deiminase (ADI-PEG20). MYC-high SCLCs are particularly sensitive to ADI-PEG20, because they lack
the enzyme argininosuccinate synthetase 1 (ASS1) that catalyzes de novo synthesis of arginine by the urea
cycle. Still, SCLC tumors eventually develop resistance to ADI-PEG20 (ADIR) that corresponds with re-
expression of ASS1. Upon ADIR, tumors acquire secondary metabolic dependencies that may be targeted to
prolong ADI-PEG20 response and patient survival. Preliminary data show that ADIR SCLC depends on serine
and one-carbon (1C) metabolism, which can be targeted with anti-folates. Preliminary data also delineate
candidate transcriptional regulators that may govern ADIR in SCLC. Activating transcription factor 4 (ATF4), a
stress-responsive transcription factor, is one predicted upstream regulator of gene programs enriched in ADIR
vs naïve SCLCs—determined by bulk and single-cell RNA sequencing. ATF4 is induced upon acute arginine
deprivation in SCLC and continues to be expressed with its target genes during ADIR. Here, the applicant will
employ a single-cell RNA-seq-derived model of SCLC response to ADI-PEG20, metabolite profiling, in vivo
isotope tracing, and CRISPR-based gene editing to interrogate whether ATF4 governs ADIR. The hypothesis for
this research is that ATF4 drives ADIR by enhancing serine and 1C metabolism in an ASS1-dependent manner.
Experiments will be performed in two specific aims to test whether ATF4 governs: 1) the sensitivity of MYC-high
SCLCs to ADI-PEG20, and/or 2) the sensitivity of ADIR SCLCs to 1C metabolism inhibitors. Knowledge gleaned
from this research will inform combination treatment strategies that improve the efficacy of ADI-PEG20 and
extend survival of patients with SCLC and other ASS1-low tumors. The proposed research will provide unique
opportunities for the applicant to gain expertise in cancer biology, cancer metabolism, and computational
analysis of -omics data—three major goals of the applicant’s training plan. The proposed research will occur
over three years of training at Huntsman Cancer Institute and the University of Utah, a collaborative and
resource-rich training environment, in the lab of Dr. Trudy Oliver.
项目摘要
小细胞肺癌(SCLC)是一种致命的神经内分泌肺肿瘤,由于以下原因治疗起来具有挑战性
早期转移、快速生长以及缺乏易于靶向的驱动改变。在过去约 40 年里,SCLC
在临床上主要将其作为单一疾病进行治疗,采用基于铂类的联合化疗,
中位生存期仅为约 10-12 个月。必须更好地了解 SCLC 生物学,以实现
开发新的治疗策略,有效延长患者的生存期。 SCLC 肿瘤扩增或
过度表达一种致癌 MYC 家族成员:MYC、MYCL 或 MYCN。 MYC 高的 SCLC 具有代谢性
与 MYC-low 不同,并且具有特定的、可针对的代谢脆弱性。最有效的治疗方法
临床前试验中治疗高 MYC SCLC 的策略是通过聚乙二醇化剥夺循环精氨酸
精氨酸脱亚胺酶(ADI-PEG20)。 MYC 高的 SCLC 对 ADI-PEG20 特别敏感,因为它们缺乏
精氨酸琥珀酸合成酶 1 (ASS1),催化尿素从头合成精氨酸
循环。尽管如此,SCLC 肿瘤最终会对 ADI-PEG20 (ADIR) 产生耐药性,这与重新
ASS1 的表达。 ADIR 后,肿瘤获得次级代谢依赖性,可能针对
延长 ADI-PEG20 反应和患者生存期。初步数据表明 ADIR SCLC 依赖于丝氨酸
和一碳(1C)代谢,可以用抗叶酸药物来靶向。初步数据也描绘了
可能控制 SCLC 中 ADIR 的候选转录调节因子。激活转录因子 4 (ATF4)
应激反应转录因子,是一种预测的富含 ADIR 的基因程序上游调节因子
与初始 SCLC——通过批量和单细胞 RNA 测序确定。 ATF4 由急性精氨酸诱导
SCLC 中的剥夺并在 ADIR 期间继续与其靶基因一起表达。在此,申请人将
采用单细胞 RNA-seq 衍生的 SCLC 对 ADI-PEG20 反应的模型,体内代谢物分析
同位素追踪和基于 CRISPR 的基因编辑来询问 ATF4 是否控制 ADIR。假设为
这项研究表明,ATF4 通过以 ASS1 依赖性方式增强丝氨酸和 1C 代谢来驱动 ADIR。
实验将针对两个特定目标进行,以测试 ATF4 是否具有控制作用:1)MYC-high 的敏感性
SCLC 对 ADI-PEG20 的敏感性,和/或 2) ADIR SCLC 对 1C 代谢抑制剂的敏感性。收集到的知识
这项研究将为联合治疗策略提供信息,以提高 ADI-PEG20 的疗效和
延长 SCLC 和其他 ASS1 低肿瘤患者的生存期。拟议的研究将提供独特的
申请人有机会获得癌症生物学、癌症代谢和计算方面的专业知识
组学数据分析——申请人培训计划的三个主要目标。拟议的研究将发生
在亨茨曼癌症研究所和犹他大学接受了三年多的培训,这是一个合作和
资源丰富的培训环境,在Trudy Oliver博士的实验室。
项目成果
期刊论文数量(0)
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ABBIE SHAYE IRELAND其他文献
ABBIE SHAYE IRELAND的其他文献
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{{ truncateString('ABBIE SHAYE IRELAND', 18)}}的其他基金
Investigating and targeting metabolic vulnerabilities of MYC-driven small cell lung cancer
研究和针对 MYC 驱动的小细胞肺癌的代谢脆弱性
- 批准号:
10535989 - 财政年份:2022
- 资助金额:
$ 4.77万 - 项目类别:
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