Mechanisms of response and resistance to KRAS inhibition in pancreatic cancer
胰腺癌中 KRAS 抑制的反应和耐药机制
基本信息
- 批准号:10566224
- 负责人:
- 金额:$ 56.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:ARID1A geneBiological AssayBiological MarkersBiopsyCDKN2A geneCell Cycle ProgressionCellsClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyDNA DamageDataDevelopmentDiseaseEngineeringFoundationsFutureGenesGeneticGenetic DeterminismGenetic MarkersGenetic TranscriptionGenomic approachGenomicsGenotypeGoalsHumanIn VitroKPC modelKRAS oncogenesisKRAS2 geneKRASG12DMADH4 geneMAP Kinase GeneMalignant NeoplasmsMalignant neoplasm of pancreasModelingMolecularMusMutationNeuronsOncogenicOncoproteinsOrganoidsPancreatic Ductal AdenocarcinomaParacrine CommunicationPathway interactionsPatientsPharmaceutical PreparationsPhenotypePrognosisRAS inhibitionRas InhibitorResistanceRoleScreening ResultShapesSignal TransductionSystemTP53 geneTherapeuticTherapeutic InterventionTreatment EfficacyTumor Suppressor GenesTumor Suppressor Proteinscancer cellcancer typeclinically relevantdrug sensitivityeffective therapyfunctional genomicsgenetic approachhuman RNA sequencinghuman datahuman modelin vivoinhibitorinnovationknockout genemolecular subtypesmouse modelmutantneoplastic cellnovelnovel therapeutic interventionnovel therapeuticspancreatic cancer modelpancreatic cancer patientspancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelparacrinepredictive markerprogramsreplication stressresearch clinical testingresistance mechanismresponsesingle-cell RNA sequencingsmall molecule inhibitortargeted treatmenttransplant modeltreatment responsetumortumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer, with a five-year survival of only 10%. There
is an urgent need to develop new therapeutic strategies for this disease. Oncogenic KRAS mutations occur in
most patients and co-occur with alterations in several different tumor suppressor genes, including TP53,
CDKN2A, SMAD4, ARID1A and others. Multiple different transcriptional subtypes of PDAC have also been
observed, such as the classical and basal-like programs, which define distinct subsets of disease with differing
prognosis and therapeutic response. The recent development of new small molecule inhibitors of KRAS that
target KRAS mutations frequently observed in PDAC has the potential to transform the treatment of this disease.
We and others have shown that primary and acquired resistance mechanisms can limit the clinical benefit of
KRAS inhibitor monotherapy in cancer; thus, understanding the mechanisms of response and resistance to
KRAS inhibition in PDAC will be critical to maximize the potential of these therapies. This proposal will use novel
mutant-selective KRAS and pan-RAS inhibitors, unique human organoid and mouse models of PDAC, and
innovative single-cell and functional genomic approaches to define the genetic, transcriptional and
microenvironmental factors that impact response to KRAS inhibition in PDAC. In Aim 1 we will investigate how
tumor suppressor genotype can modify response to KRAS inhibition using CRISPR-Cas12a tumor suppressor
gene knockout screens in both in vitro and in vivo systems to simultaneously model multiple PDAC genotypes
and systematically define genetic biomarkers and mechanisms of sensitivity or resistance to KRAS inhibition. In
Aim 2, we will define the role of PDAC transcriptional cell state in modifying response to KRAS inhibition using
novel isogenic murine PDAC organoids and human patient-derived PDAC organoids representing the basal-like,
classical and neuronal-like subtypes of PDAC. We will characterize subtype-specific adaptive mechanisms of
response to KRAS inhibition and evaluate subtype plasticity with a goal to develop combination therapy
strategies with KRAS inhibition to target each subtype. In Aim 3, we will build on preliminary single-cell RNA
sequencing (scRNA-seq) data from human PDAC biopsies showing that the tumor microenvironment (TME)
shapes the transcriptional phenotype and therapeutic response of PDAC cells. We will examine response to
oncogenic Kras inhibition in new mouse models of the basal-like, classical and neuronal-like subtypes of PDAC
and will interrogate the role of paracrine signaling mechanisms from the TME in modifying malignant cell state
and response to KRAS inhibition using ex vivo scRNA-seq and drug sensitivity profiling assays. Collectively,
these studies will form a foundation for development of new biomarkers and combination therapies with KRAS
inhibition that can be evaluated in future clinical trials for PDAC patients.
项目总结/摘要
胰腺导管腺癌(PDAC)是一种毁灭性的癌症,五年生存率仅为10%。那里
因此,迫切需要开发新的治疗策略。致癌性KRAS突变发生在
大多数患者与几种不同肿瘤抑制基因的改变同时发生,包括TP 53,
CDKN 2A、SMAD 4、ARID 1A等。PDAC的多种不同转录亚型也已被发现。
观察到的,如经典和基础样程序,定义了不同的疾病子集,
预后和治疗反应。最近开发的新的小分子KRAS抑制剂,
在PDAC中经常观察到的靶向KRAS突变有可能改变这种疾病的治疗。
我们和其他人已经表明,原发性和获得性耐药机制可能会限制药物的临床益处
KRAS抑制剂单药治疗癌症;因此,了解对
PDAC中的KRAS抑制对于最大化这些疗法的潜力至关重要。该提案将使用新的
多药选择性KRAS和泛RAS抑制剂,独特的人类类器官和PDAC小鼠模型,以及
创新的单细胞和功能基因组方法,以确定遗传,转录和
影响PDAC中KRAS抑制反应的微环境因素。在目标1中,我们将研究如何
肿瘤抑制基因型可以使用CRISPR-Cas 12 a肿瘤抑制因子改变对KRAS抑制的反应
在体外和体内系统中进行基因敲除筛选以同时模拟多种PDAC基因型
并系统地定义对KRAS抑制的敏感性或抗性的遗传生物标志物和机制。在
目的2,我们将定义PDAC转录细胞状态在修饰对KRAS抑制的反应中的作用,
新的等基因鼠PDAC类器官和人患者衍生的PDAC类器官代表基底样,
PDAC的经典亚型和神经元样亚型。我们将描述特定亚型的适应机制,
对KRAS抑制的反应并评估亚型可塑性,目标是开发联合治疗
针对每种亚型的KRAS抑制策略。在目标3中,我们将建立在初步的单细胞RNA基础上,
来自人类PDAC活检的scRNA-seq测序数据显示,肿瘤微环境(TME)
形成PDAC细胞的转录表型和治疗反应。我们将研究对以下问题的反应:
PDAC基底样、经典和神经元样亚型新小鼠模型中的致癌Kras抑制
并将询问来自TME的旁分泌信号传导机制在改变恶性细胞状态中的作用
以及使用离体scRNA-seq和药物敏感性分析测定对KRAS抑制的应答。总的来说,
这些研究将为开发新的生物标志物和与KRAS联合治疗奠定基础
抑制,可以在未来的临床试验中评估PDAC患者。
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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Andrew James Aguirre其他文献
Andrew James Aguirre的其他文献
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{{ truncateString('Andrew James Aguirre', 18)}}的其他基金
Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity
胰腺癌恶性细胞状态的基质调节和治疗敏感性
- 批准号:
10517569 - 财政年份:2022
- 资助金额:
$ 56.18万 - 项目类别:
Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity
胰腺癌恶性细胞状态的基质调节和治疗敏感性
- 批准号:
10706519 - 财政年份:2022
- 资助金额:
$ 56.18万 - 项目类别:
Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancer
KRAS 突变胰腺癌表观遗传脆弱性的功能研究
- 批准号:
10221636 - 财政年份:2017
- 资助金额:
$ 56.18万 - 项目类别:
Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancer
KRAS 突变胰腺癌表观遗传脆弱性的功能研究
- 批准号:
9370987 - 财政年份:2017
- 资助金额:
$ 56.18万 - 项目类别:
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