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)是一种致命性的神经内分泌肺癌,其治疗具有挑战性。
早期转移,生长迅速,缺乏易于靶向的驱动因素改变。在过去的40年里,SCLC
在临床上主要作为单一疾病与以铂为基础的联合化疗进行治疗
中位生存期仅为约10-12个月。必须更好地了解小细胞肺癌生物学,才能
开发新的治疗策略,有效地延长患者的生存时间。小细胞肺癌肿瘤放大或
过表达一个致癌的MYC家族成员:MYC、MYCL或MYCN。MYC-高SCLC在代谢过程中
不同于MYC-LOW,具有特定和有针对性的代谢脆弱性。最有效的治疗方法
临床前试验中治疗MYC高SCLC的策略是聚乙二醇化去循环精氨酸
精氨酸脱亚胺酶(ADI-PEG20)。高MYC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
周而复始。尽管如此,小细胞肺癌最终对ADI-PEG20(ADIR)产生耐药,这与Re-PEG20相对应。
ASS1的表达。在ADIR后,肿瘤获得可能被靶向的次级代谢依赖
延长ADI-PEG20反应和患者生存时间。初步数据显示ADIR SCLC依赖丝氨酸
和一碳(1C)代谢,这可以作为抗叶酸的靶点。初步数据还描绘了
候选转录调控因子可能在小细胞肺癌中调控ADIR。激活转录因子4(ATF4),
逆境反应转录因子,是富含ADIR的基因程序的上游调控因子
VS幼稚的SCLC-通过散装和单细胞RNA测序确定。急性精氨酸诱导的血管紧张素转换酶4
在小细胞肺癌中被剥夺,并且在ADIR期间继续与其靶基因一起表达。在这里,申请者将
采用单细胞RNA序列衍生的小细胞肺癌对ADI-PEG20的反应模型,体内代谢物分析
同位素追踪,以及基于CRISPR的基因编辑,以询问ATF4是否统治ADIR。假设
这项研究表明,ATF4通过促进ASS1依赖的丝氨酸和1C代谢来驱动ADIR。
实验将在两个特定的目标下进行,以测试ATF4是否支配: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
从这项研究将提供联合治疗策略,以提高ADI-PEG20和
延长小细胞肺癌和其他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、癌症新陈代谢和计算机方面的专业知识
分析--组学数据--申请人培训计划的三个主要目标。拟议的研究将会进行
在亨斯迈癌症研究所和犹他大学接受了三年多的培训,合作和
资源丰富的培训环境,在特鲁迪·奥利弗博士的实验室里。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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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