CLINCIAL VALIDATION OF APC AND TP53 AS BIOMARKERS FOR CETUXIMAB RESPONSE
APC 和 TP53 作为西妥昔单抗反应生物标志物的临床验证
基本信息
- 批准号:10381742
- 负责人:
- 金额:$ 29.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-03 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:APC geneAgeAllelesArchivesBRAF geneBiological AssayBiological MarkersCancer and Leukemia Group BCaringCell LineCertificationCetuximabClinicClinicalClinical TrialsCodeColorectal CancerConsensus SequenceCyclophosphamideDNA sequencingDataDrug UtilizationEngineeringEnsureEnvironmentEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorFDA approvedFormalinFreezingFundingGene Expression ProfileGene FrequencyGenesGenotypeGoldHumanIn VitroKRAS2 geneKnowledgeLaboratoriesLeftLesionMeasuresModelingMolecularMutateMutationMutation DetectionNegative FindingObservational StudyOncogenesOutcomeParaffin EmbeddingPatient RecruitmentsPatient SelectionPatientsPerformancePharmacologic SubstancePhasePublishingRas/RafReportingReproducibilityResearch PersonnelResistanceRoleSamplingSensitivity and SpecificitySideTP53 geneTestingThe Cancer Genome AtlasTherapeuticTissue SampleTranslatingTreatment outcomeTumor Suppressor GenesValidationWorkagedbasecancer geneticsclinical practicecohortcolon cancer patientscolorectal cancer treatmentcost effectiveexperiencegenetic predictorsimprovedindexinginhibitor therapymetastatic colorectalmutantpanitumumabprognosticrapid testresponsetherapeutic targettumortumor heterogeneity
项目摘要
PROJECT SUMMARY/ABSTRACT
The objective of this combined UH2/UH3 application is to develop a cost-effective, rapid, test that can be
rapidly translated to the clinic and ultimately be used to re-purpose a class of FDA-approved colorectal
cancer (CRC) EGFR inhibitor (EGFRi) therapeutics (cetuximab and panitumumab). To date, only negative
genetic predictors (mutant KRAS/NRAS) of EGFRi response have been employed clinically, currently
restricting EGFRi use to wild-type RAS/RAF subpopulations, and more recently, just to “left-sided” lesions.
We recently reported a new prognostic role for APC that relates to the number of alleles mutated and to the
association with other mutant genes such as KRAS and TP53 (Nat Commun, 2016). Further analysis also
revealed that mutant APC (A) genotypes, in combination with mutant TP53 (P), are strongly correlated with a
gene expression signature measuring cetuximab sensitivity (CTX-S). These data led to the provocative
hypothesis that mutant APC + TP53 (AP) genotypes together---more so than either mutant gene alone (A_ /
_P), or wild-type AP (_ _)---may have a new role in positively-predicting EGFRi outcomes (Nat Commun,
Under Review, 2018). This hypothesis is based on 3 key observations we have recently made in our cohort
and in TCGA data:
(1) CTX-S scores are significantly higher in: AP > A_ / _P > _ _ tumors in both WT and MUT KRAS tumors;
(2) AP mutations are more frequent in Left (cetuximab-sensitive) > Right (cetuximab-resistant) CRC;
(3) AP mutations are almost non-existent in MSI tumors (highly cetuximab-resistant).
These findings have two potentially high-impact clinical implications: (1) they re-define the patient selection
strategy by further restricting EGFRi therapies to wild-type RAS/RAF patients harboring AP mutations, thereby
increasing response rates; (2) they could expand the therapeutic opportunity to treat a substantial number of
previously-excluded mutant KRAS/NRAS patients who have AP mutations in both left and right CRCs. If the
test for these mutations is developed and clinically validated, the utilization of these drugs could be expanded
to ~25% more patients, including more first-line patients. For the vast majority of CRC patients, AP
mutations are not assessed in current practice. Unlike KRAS/NRAS oncogenes, both A and P are tumor
suppressor genes that can have a multitude of inactivating mutations that must be detected. Thus, there is an
opportunity to change clinical practice and standards of care to ultimately improve CRC outcomes with a new
test.
In the LabCorp CAP/CLIA environment, we plan to develop a new highly sensitive, specific and cost-effective
targeted DNA-sequencing “assay” to detect mutations in the coding regions of the principal genes APC, TP53,
KRAS, BRAF, NRAS from formalin fixed paraffin embedded (FFPE) tissue samples.
In the UH2 Phase of this proposal, a new FFPE targeted DNA sequencing assay, with greater potential to
accurately detect mutations at low allelic frequencies, will be analytically validated with the following
approaches so that it can be offered in a CAP/CLIA laboratory for testing clinical samples:
(1) A variety of cell lines, both native and engineered, will be used to ensure analytic sensitivity, specificity, and
reproducibility.
(2) ~100 formalin fixed paraffin embedded (FFPE) samples of variable age, quality, tumor heterogeneity,
grade, and stage matched to the highest quality, “gold standard” fresh frozen (FF) samples from the same
originating tumor will be used to assess assay performance.
In the UH3 Phase, we plan to perform clinical validation of the test developed in the UH2 Phase to provide
evidence that the presence of AP mutations may predict EGFRi responses translating into improved clinical
outcomes. Here, we will demonstrate that assay of APC and TP53 genotypes along with those already
performed as SOC (KRAS/NRAS/BRAF) can be clinically validated (i.e. used to predict cetuximab
sensitivity/response) using human samples derived from:
(1) a retrospective CRC observational study relating CRC genetics to predicted cetuximab sensitivity.
(2) a historical NCI trial (CALGB 80203) where patients were treated with cetuximab but were not sequenced.
项目摘要/摘要
这种组合UH2/UH3应用的目标是开发一种成本效益高、快速、可以
迅速转化到临床,并最终用于重新调整FDA批准的一类结直肠癌的用途
癌症(CRC)、EGFR抑制剂(EGFRi)治疗药物(西妥昔单抗和帕尼单抗)。到目前为止,只有负值
目前,EGFRi反应的遗传预测因子(突变的KRAS/NRAS)已应用于临床
限制EGFRi用于野生型RAS/RAF亚群,最近,仅限于“左侧”皮损。
我们最近报道了APC的一个新的预后作用,它与突变的等位基因数量和
与KRAS和TP53等其他突变基因的相关性(NAT Commun,2016)。进一步的分析也
突变型APC(A)和突变型TP53(P)与APC(A)突变密切相关。
西妥昔单抗敏感性测定的基因表达特征(CTX-S)。这些数据导致了挑衅性的
假设突变的APC+TP53(AP)基因同时存在-比任何一个突变基因单独存在更严重(A_/
_P)或野生型AP(__)-可能在积极预测EGFRi结果方面有新的作用(NAT Commun,
正在审查中,2018年)。这一假设是基于我们最近在我们的队列中所做的三个关键观察
在TCGA数据中:
(1)WT和MUT KRAS肿瘤中AP>、A_/_P>、MUT-KRAS肿瘤CTX-S评分均较高;
(2)AP突变多见于左侧(西妥昔单抗敏感)和右侧(西妥昔单抗耐药);
(3)在西妥昔单抗高度耐药的MSI肿瘤中几乎不存在AP突变。
这些发现有两个潜在的高影响的临床意义:(1)它们重新定义了患者的选择
通过进一步限制EGFRi治疗携带AP突变的野生型RAS/RAF患者的策略,从而
提高应答率;(2)它们可以扩大治疗机会,治疗大量的
之前排除的突变的KRAS/NRAS患者,在左侧和右侧的CRC中都有AP突变。如果
对这些突变的检测已经开发出来并得到了临床验证,这些药物的用途可能会扩大
增加约25%的患者,包括更多的一线患者。对于绝大多数的结直肠癌患者,AP
在目前的实践中,没有对突变进行评估。与KRAS/NRAS癌基因不同,A和P都是肿瘤
抑制基因可能有大量必须检测到的失活突变。因此,有一个
有机会改变临床实践和护理标准,最终通过新的
测试。
在LabCorp CAP/CLIA环境中,我们计划开发一种新的高度敏感、特定和成本效益高的
靶向DNA测序法检测主要基因APC,TP53,
福尔马林固定石蜡包埋(FFPE)组织标本中的KRAS、BRAF、NRAS。
在这项提案的UH2阶段,一种新的FFPE靶向DNA测序分析,具有更大的潜力
准确检测低等位基因频率的突变,将通过以下分析验证
方法,以便在CAP/CLIA实验室中提供它来测试临床样本:
(1)将使用各种细胞系,包括天然的和工程的,以确保分析的敏感性、特异性和
再现性。
(2)~100份福尔马林固定石蜡包埋(FFPE)标本,年龄、质量、肿瘤异质性、
等级和阶段与最高质量匹配,来自相同的“黄金标准”新鲜冷冻(FF)样品
原始肿瘤将被用来评估检测性能。
在UH3阶段,我们计划对在UH2阶段开发的测试进行临床验证,以提供
AP突变的存在可以预测EGFRi反应转化为临床改善的证据
结果。在这里,我们将演示APC和TP53基因分析以及那些已经存在的
作为SOC(KRAS/NRAS/BRAF)执行可经临床验证(即用于预测西妥昔单抗
灵敏度/响应)使用来自以下来源的人体样本:
(1)一项关于结直肠癌遗传学与预测西妥昔单抗敏感性的回顾性CRC观察性研究。
(2)一项既往的NCI试验(CALGB 80203),其中患者接受西妥昔单抗治疗,但未进行测序。
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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TIMOTHY J YEATMAN的其他文献
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{{ truncateString('TIMOTHY J YEATMAN', 18)}}的其他基金
CLINCIAL VALIDATION OF APC AND TP53 AS BIOMARKERS FOR CETUXIMAB RESPONSE
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:
10789666 - 财政年份:2023
- 资助金额:
$ 29.88万 - 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
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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
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10613171 - 财政年份:2021
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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:
10289625 - 财政年份:2021
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$ 29.88万 - 项目类别:
CLINCIAL VALIDATION OF APC AND TP53 AS BIOMARKERS FOR CETUXIMAB RESPONSE
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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INDIVIDUALIZING COLON CANCER THERAPY USING HYBRID RNA AND DNA MOLECULAR SIGNATURE
利用混合 RNA 和 DNA 分子特征进行个体化结肠癌治疗
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8738408 - 财政年份:2012
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INDIVIDUALIZING COLON CANCER THERAPY USING HYBRID RNA AND DNA MOLECULAR SIGNATURE
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