Dissecting and targeting tumor-TME crosstalk to forestall acquired KRASG12C inhibitor resistance in NSCLC.
剖析和靶向肿瘤-TME 串扰,以预防 NSCLC 中获得性 KRASG12C 抑制剂耐药性。
基本信息
- 批准号:10634271
- 负责人:
- 金额:$ 37.06万
- 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:2023-05-17 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAnimal ModelArchitectureAutopsyBioinformaticsBiologyBiometryBiopsyBypassCancer CenterCancer PatientCellsCessation of lifeClinicalDNA Sequence AlterationDataDependenceDevelopmentExtinctionFailureGenetic EngineeringGenomicsImmuneImmunobiologyImmunocompetentImmunogenomicsImmunology procedureIn VitroKRAS2 geneMAP Kinase GeneMalignant NeoplasmsMediatorMedical OncologyModelingMolecularMusMutationNon-Small-Cell Lung CarcinomaOncogenicOncoproteinsPathway interactionsPatient-Focused OutcomesPatientsPhasePhosphorylationPre-Clinical ModelPropertyPublicationsRadiology SpecialtyRefractoryReportingResistanceResolutionRoleSTAT3 geneSTK11 geneSamplingShapesSignal TransductionSpecimenTP53 geneTherapeuticTimeTumor EscapeTumor Suppressor GenesTyrosineWorkbiobankclinical developmentclinical efficacyclinically significantimprovedindividual responseinhibitorinhibitor therapyinsightmolecular pathologymouse modelmutantneoplastic cellnon-geneticnovelnovel therapeutic interventionobjective response ratepreventresistance mechanismresponsesingle-cell RNA sequencingsmall moleculestandard of caresynergismtargeted cancer therapytherapeutic targettumortumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
Oncogenic KRASG12C (KG12C) mutations underpin the development of ~14% of non-squamous non-small cell lung
cancer (NSCLC) and account for ~10,000 deaths annually in the U.S. The development of potent, selective and
clinically active covalent inhibitors of the KG12C oncoprotein represents one of the most exciting recent advances
in the field of targeted cancer therapy, yet strategies to circumvent the development of adaptive resistance and
improve the durability of individual responses to KG12C inhibitors are urgently needed in order to transform clinical
outcomes for patients. The role of crosstalk between tumor cells and the tumor microenvironment (TME) in the
development of acquired KG12C inhibitor resistance in NSCLC has not been systematically examined to date,
despite evidence that in more than 50% of cases no genomic resistance mechanisms can be identified at the
time of radiological progression. Furthermore, key mediators of TME remodeling and immune escape in
response to KG12C inhibitor therapy remain poorly defined and therapeutic strategies that target the adverse TME
in order to prevent, delay or overcome KG12C inhibitor adaptation/acquired resistance have not been established.
Finally, the impact of major co-occurring genomic alterations in STK11/LKB1 and TP53 and that shape the
immune contexture of KRAS-mutant NSCLC– on non-genetic mechanisms of acquired KG12C inhibitor resistance
is not known. Based on our preliminary findings and previous work we hypothesize that: 1. Remodeling of the
tumor microenvironment and immune escape can promote non-tumor cell autonomous adaptation/acquired
resistance to KG12C inhibitors; 2. Targeting STAT3 signaling with TTI-101 can forestall and possibly overcome
non-genetic acquired resistance to KG12C inhibitors through effects on tumor cells and/or the TME. In Aim 1, we
will determine the contribution of TME remodeling and immune escape to acquired KG12C inhibitor resistance in
NSCLC, using immune competent models of KG12C NSCLC that recapitulate its co-mutational complexity. We will
further interrogate the role of master mediators of TME adaptive remodeling with initial focus on STAT3 and we
will validate key findings using paired biopsies from patients with metastatic KG12C-mutant NSCLC that were
treated with sotorasib as part of standard of care. In Aim 2, we will evaluate the anti-tumor efficacy and TME-
modifying effects of STAT3 inhibition with TTI-101 in combination with direct KG12C inhibitors in immune-
competent models of KG12C NSCLC. Clinical significance: This work will yield fresh insights into non-genetic
mechanisms of acquired resistance to KG12C inhibitors that rely on tumor-TME crosstalk and will facilitate the
development of novel therapeutic strategies that tackle the adverse TME in order to maximize long-term clinical
benefit from KG12C inhibitors.
项目概要/摘要
致癌 KRASG12C (KG12C) 突变支撑约 14% 的非鳞状非小细胞肺的发育
癌症 (NSCLC) 每年导致美国约 10,000 人死亡。
KG12C 癌蛋白的临床活性共价抑制剂代表了最新最令人兴奋的进展之一
在靶向癌症治疗领域,还存在规避适应性耐药性和
为了改变临床现状,迫切需要提高个体对 KG12C 抑制剂反应的持久性
患者的结果。肿瘤细胞与肿瘤微环境(TME)之间的串扰在
迄今为止,尚未系统地检查 NSCLC 中获得性 KG12C 抑制剂耐药性的发展,
尽管有证据表明,在超过 50% 的病例中,无法在基因组中识别出耐药机制
放射学进展的时间。此外,TME 重塑和免疫逃逸的关键介质
对 KG12C 抑制剂治疗的反应仍不明确,针对不良 TME 的治疗策略
尚未确定如何预防、延迟或克服 KG12C 抑制剂适应/获得性耐药性。
最后,STK11/LKB1 和 TP53 中主要同时发生的基因组改变的影响以及塑造
KRAS 突变 NSCLC 的免疫环境——关于获得性 KG12C 抑制剂耐药性的非遗传机制
尚不清楚。根据我们的初步发现和之前的工作,我们假设: 1. 重塑
肿瘤微环境和免疫逃逸可促进非肿瘤细胞自主适应/获得性
对 KG12C 抑制剂的耐药性; 2. 使用 TTI-101 靶向 STAT3 信号传导可以预防并可能克服
通过对肿瘤细胞和/或 TME 的影响,获得对 KG12C 抑制剂的非遗传性耐药性。在目标 1 中,我们
将确定 TME 重塑和免疫逃逸对获得性 KG12C 抑制剂耐药性的贡献
NSCLC,使用 KG12C NSCLC 的免疫活性模型来概括其共突变复杂性。我们将
进一步询问 TME 适应性重塑的主要介导者的作用,最初关注 STAT3,我们
将使用来自转移性 KG12C 突变 NSCLC 患者的配对活检来验证关键发现,这些患者是
作为标准护理的一部分,使用 sotorasib 进行治疗。在目标2中,我们将评估抗肿瘤功效和TME-
TTI-101 与直接 KG12C 抑制剂联合使用可改变免疫组化中 STAT3 抑制的效果
KG12C NSCLC 的感受态模型。临床意义:这项工作将为非遗传性疾病带来新的见解
对 KG12C 抑制剂的获得性耐药机制依赖于肿瘤-TME 串扰,并将促进
开发新的治疗策略来解决不良 TME,以最大限度地提高长期临床效果
受益于 KG12C 抑制剂。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ferdinandos Skoulidis其他文献
Ferdinandos Skoulidis的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ferdinandos Skoulidis', 18)}}的其他基金
Dissecting and targeting mechanisms of genomic instability-triggered immune evasion in RBM10-deficient non-small cell lung cancer
RBM10 缺陷型非小细胞肺癌基因组不稳定性触发免疫逃逸的剖析和靶向机制
- 批准号:
10658049 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
Understanding and harnessing immune-modulatory effects of covalent KRASG12C inhibitors in KRASG12C-mutant non-small cell lung cancer
了解和利用共价 KRASG12C 抑制剂对 KRASG12C 突变非小细胞肺癌的免疫调节作用
- 批准号:
10478950 - 财政年份:2021
- 资助金额:
$ 37.06万 - 项目类别:
Understanding and harnessing immune-modulatory effects of covalent KRASG12C inhibitors in KRASG12C-mutant non-small cell lung cancer
了解和利用共价 KRASG12C 抑制剂对 KRASG12C 突变非小细胞肺癌的免疫调节作用
- 批准号:
10675537 - 财政年份:2021
- 资助金额:
$ 37.06万 - 项目类别:
Understanding and harnessing immune-modulatory effects of covalent KRASG12C inhibitors in KRASG12C-mutant non-small cell lung cancer
了解和利用共价 KRASG12C 抑制剂对 KRASG12C 突变非小细胞肺癌的免疫调节作用
- 批准号:
10276919 - 财政年份:2021
- 资助金额:
$ 37.06万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 37.06万 - 项目类别:
Grant-in-Aid for Early-Career Scientists