Detection of Colorectal Cancer Adaptive Mutability May Justify Combination of Targeted- and Immune-Therapies
结直肠癌适应性突变的检测可能证明靶向治疗和免疫治疗相结合的合理性
基本信息
- 批准号:10289627
- 负责人:
- 金额:$ 6.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-20 至 2022-04-16
- 项目状态:已结题
- 来源:
- 关键词:BRAF geneBiological AssayBiological MarkersBiological SciencesCancer EtiologyCancer cell lineCell LineCellsCessation of lifeColorectal CancerCombined Modality TherapyComplexDNADNA Repair GeneDNA sequencingDataDependenceDiagnosisDrug ToleranceDrug resistanceEpidermal Growth Factor ReceptorExposure toGene Expression ProfileGene FrequencyGenesGeneticGenomeImmuneImmune checkpoint inhibitorImmunotherapyIndividualKRAS2 geneLeadMEKsMeasurableMeasuresMediatingMicrosatellite InstabilityMismatch RepairMolecularMolecular TargetMutateMutationOncogenesOrganoidsPathway interactionsPatientsPharmaceutical PreparationsPhenotypePolymerasePopulationProbabilityRas InhibitorRas Signaling PathwayRas/RafReactive Oxygen SpeciesReportingResistanceSignal PathwaySignal TransductionSolidTechnologyTestingTimebasebiological adaptation to stressbiomarker-drivencancer cellcheckpoint therapyclinical predictorscolon cancer cell linecolorectal cancer screeningdetection limitexperimental studygene panelgenetic variantgenome-widegenotoxicityhomologous recombinationimmune checkpointimmunogenicityimprovedinhibitor/antagonistmutantmutational statusneoantigensnovelnovel therapeuticspatient subsetspredicting responsepredictive markerrepair enzymeresistance mechanismresponsesoundtargeted agenttargeted treatmenttherapeutic targettranscriptome sequencingtumor
项目摘要
PROJECT SUMMARY/ABSTRACT
Colorectal cancer (CRC) is a major cause of cancer deaths which is curable if detected early. Unfortunately,
many CRC tumors are diagnosed at more advanced stages where cure rates remain low with 20% five-year
survival. The EGFR/RAS signaling pathway is a strong driver of CRC when constitutively activated via mutations
(KRAS ~40%, BRAF ~10%, NRAS ~5%), but targeted molecular inhibitors, when used alone (EGFRi, BRAFi,
MEKi or ERKi), have yielded disappointing survival benefit. To date, it remains difficult to identify the subset of
patients who will meaningfully benefit from EGFR/RAS pathway-targeted therapies, likely due to complex
resistance mechanisms. A widely held view is that resistance to targeted therapies is due to pre-existence of
rare, drug-resistant mutant cells (subclones) that expand and repopulate the tumor following initial successful
treatment leading to permanent, clonal resistance. Recently, however, adaptive mutability (AM) of CRC in
response to targeted therapies has been reported as a novel, early resistance mechanism. This hypothesis
proposes that blocking critical, hard-wired signaling pathways causes a “stress” reaction characterized by the of
genotoxic, reactive oxygen species (ROS) and the suppression of DNA mismatch repair enzymes. These early
drug-induced changes effectively cause a sub-clonal, hypermutable state that facilitates the eventual emergence
of permanently drug-resistant clones. Microsatellite instability (MSI) and other mutator states (i.e. POLE-mutated
tumors) are now known to provide a greater probability of checkpoint inhibitor responses. Thus, we hypothesize
that the AM induced by EGFR/RAS pathway inhibitors may lead to rapid, sub-clonal, enhanced mutability, and
a higher load of neoantigens producing an “MSI-like” state. This hypermutability, if detectable, would portend
the higher likelihood of response to checkpoint inhibitors. Traditional analysis of tumor mutation burden (TMB)
by NGS assessment of a cancer gene panel would not likely detect genome-wide sub-clonal TMB (scTMB).
Standard TMB assays detect bountiful, clonally-expanded mutations fixed in the tumor from the time of its
founding. Conversely, we propose that the mutations resulting from a rapid, drug-induced mutator phenotype
will likely be present at low variant allele frequencies (i.e. subclonal) that are below the limit of detection of
standard NGS approaches. In this proposal, we will test the hypothesis that scTMB occurs in response to
targeted therapies, and can be detected using an ultrasensitive and highly specific genome-wide Duplex DNA
sequencing assay as an indicator (biomarker) of a mutator state induced by targeted therapies. We propose that
the presence of scTMB would predict responses to checkpoint inhibitors, and suggest a benefit to targeted
therapies combined with checkpoint inhibitors. These studies will lead to a better molecular understanding of
the newly identified “adaptive mutability” resistance mechanism, and potentially provide a solid rationale for the
use of combination targeted- and immune-therapies in biomarker-selected patient subpopulations to improve
response.
项目总结/摘要
结直肠癌(CRC)是癌症死亡的主要原因,如果早期发现,是可以治愈的。不幸的是,
许多CRC肿瘤在更晚期被诊断,其中治愈率仍然很低,
生存EGFR/RAS信号通路在通过突变组成性激活时是CRC的强驱动力
(KRAS~ 40%,BRAF ~ 10%,NRAS ~5%),但当单独使用时,靶向分子抑制剂(EGFRi,BRAFi,
MEKi或ERKi)产生了令人失望的存活益处。到目前为止,仍然很难确定
可能由于复杂的
抵抗机制一种广泛持有的观点是,对靶向治疗的耐药性是由于预先存在的
一种罕见的耐药突变细胞(亚克隆),在最初的成功治疗后,
导致永久性克隆抗性的治疗。然而,最近,CRC的自适应可变性(AM)在
对靶向治疗的反应已被报道为一种新的早期耐药机制。这一假设
提出,阻断关键的,硬连线的信号通路会导致一种“应激”反应,其特征是
基因毒性、活性氧(ROS)和DNA错配修复酶的抑制。这些早期
药物诱导的变化有效地导致亚克隆,超突变状态,促进最终出现
永久性抗药性克隆人微卫星不稳定性(MSI)和其他增变子状态(即POLE突变)
肿瘤)提供检查点抑制剂应答的更大可能性。因此,我们假设
EGFR/RAS通路抑制剂诱导的AM可能导致快速、亚克隆、增强的突变性,
产生“MSI样”状态的新抗原的较高负荷。这种超变异性,如果被检测到,
对检查点抑制剂反应的可能性越高。肿瘤突变负荷(TMB)的传统分析
通过NGS评估癌症基因组不太可能检测到全基因组亚克隆TMB(scTMB)。
标准的TMB测定检测从肿瘤形成时起就固定在肿瘤中的邦蒂富尔克隆扩增突变。
铸造.相反,我们认为,由快速的药物诱导的突变表型引起的突变,
可能以低于以下检测限的低变异等位基因频率(即亚克隆)存在:
标准NGS方法。在本提案中,我们将测试scTMB发生在响应于
靶向治疗,并可以使用超灵敏和高度特异性的全基因组双链DNA检测
测序测定作为由靶向疗法诱导的突变体状态的指示物(生物标志物)。我们建议
scTMB的存在可以预测对检查点抑制剂的反应,并表明靶向的
与检查点抑制剂联合治疗。这些研究将导致更好的分子理解
新发现的“适应性突变”抗性机制,并可能为
在生物标志物选择的患者亚群中使用组合靶向和免疫疗法以改善
反应
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('TIMOTHY J YEATMAN', 18)}}的其他基金
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APC 和 TP53 作为西妥昔单抗反应生物标志物的临床验证
- 批准号:
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- 资助金额:
$ 6.88万 - 项目类别:
APC + TP53 Combinatorial Mutations Emerging as Biomarkers to Predict EGFRI Sensitivity
APC TP53 组合突变作为预测 EGFRI 敏感性的生物标志物
- 批准号:
10610600 - 财政年份:2022
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Detection of Colorectal Cancer Adaptive Mutability May Justify Combination of Targeted- and Immune-Therapies
结直肠癌适应性突变的检测可能证明靶向治疗和免疫治疗相结合的合理性
- 批准号:
10613171 - 财政年份:2021
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APC + TP53 Combinatorial Mutations Emerging as Biomarkers to Predict EGFRI Sensitivity
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$ 6.88万 - 项目类别:
CLINCIAL VALIDATION OF APC AND TP53 AS BIOMARKERS FOR CETUXIMAB RESPONSE
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$ 6.88万 - 项目类别:
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