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
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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