Individualized monitoring of treatment response and resistance in patients with metastatic melanoma
转移性黑色素瘤患者治疗反应和耐药性的个体化监测
基本信息
- 批准号:10304535
- 负责人:
- 金额:$ 35.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAftercareArizonaAutomobile DrivingBRAF geneBiological MarkersBiopsyBlood CirculationBlood TestsBlood specimenCellsClinicClinicalClinical TrialsClonal EvolutionCollectionColorectal CancerDNADNA Sequence AlterationDNA analysisDNA sequencingDevelopmentDiagnosisDiagnosticDiseaseDisease ProgressionDisseminated Malignant NeoplasmDrug resistanceEnrollmentGenesGenomicsGenotypeGoalsHeterogeneityImageImmune systemImmunotherapyJAK1 geneJAK2 geneMEKsMalignant NeoplasmsMeasuresMedicineMetastatic MelanomaMethodsMolecularMolecular TargetMonitorMutationNeoplasm MetastasisObservational StudyPD-1 inhibitorsPathway interactionsPatient SelectionPatientsPlasmaPrediction of Response to TherapyPredictive ValuePrivatizationProgression-Free SurvivalsRecurrenceResistanceResistance developmentResolutionSamplingSelection for TreatmentsSomatic MutationStable DiseaseSurrogate EndpointTestingTimeLineTissuesTreatment ProtocolsValidationacquired treatment resistanceactionable mutationanti-PD-1basecirculating biomarkersclinical developmentcohortdigitaleffective therapyexomeexome sequencingfollow-upfounder mutationimprovedimproved outcomeinhibitor/antagonistlongitudinal analysismalignant breast neoplasmmelanomamelanoma biomarkersminimally invasivemolecular drug targetmolecular targeted therapiesmutantneoantigenspartial responseprospectiverecruitresponsestandard of caretargeted treatmenttherapy resistanttooltreatment responsetumortumor DNAtumor exometumor heterogeneityunnecessary treatment
项目摘要
PROJECT SUMMARY/ABSTRACT:
Metastatic melanoma is a lethal disease with a dismal 20% five-year survival. Immunotherapy and molecularly
targeted treatments improve survival but responses vary across patients and benefits are often temporary due
to disease progression. There are no established circulating biomarkers to monitor treatment response.
Molecular heterogeneity between metastatic tumors within a patient (intra-tumor heterogeneity) and treatment-
driven clonal evolution complicate choice and scheduling of treatments and limit duration of response.
Circulating levels of cancer mutations in cell-free plasma DNA (ctDNA) strongly correlate with treatment
response and disease progression in breast and colorectal cancer. The goal of this project is to assess the
utility of a ctDNA-based blood test for treatment monitoring and as a minimally-invasive alternative to tumor re-
biopsies for tumor genotyping in patients with metastatic melanoma. This goal will be pursued through analysis
of serial plasma, tumor and germline samples from patients with metastatic melanoma from three cohorts: 1) a
completed clinical trial of anti-PD1 immunotherapy; 2) prospective collection from the Stand Up To Cancer
Genomically Enabled Medicine for Melanoma trial; and 3) a prospective observational study of patients at
Mayo Clinic Arizona, treating with standard of care immunotherapy and molecularly targeted drugs.
The specific aims of this proposal are 1) to assess clinical validating of ctDNA as a biomarker for monitoring
treatment response; 2) to evaluate ctDNA sequencing as an alternative to tumor biopsies to guide treatment
selection and 3) to identify genomic drivers of acquired resistance to immunotherapy. For Aim 1, patient-
specific mutations will be identified using tumor exome sequencing, followed by targeted digital sequencing to
quantify ctDNA. Changes in ctDNA levels during treatment will be compared with response and progression on
imaging to assess clinical validity. For Aim 2, concordance of plasma and tumor samples will be assessed
using exome sequencing of pre-treatment plasma DNA and comparison with tumor exome sequencing. For
Aim 3, new genomic alterations arising at disease progression on immunotherapy will be identified using
exome sequencing of post-treatment plasma DNA. Genomic drivers of acquired resistance to anti-PD1
inhibitors will be identified by evaluating molecular pathways recurrently altered at disease progression across
the cohort.
At completion of this project, it is anticipated that the extent to which ctDNA analysis is useful in melanoma for
tumor monitoring, as an alternative to (and potential improvement) over tumor re-biopsies for patient selection
and as an approach for investigating acquired resistance to immunotherapy, will be established.
项目总结/摘要:
转移性黑色素瘤是一种致命的疾病,五年生存率只有20%。免疫治疗和分子
有针对性的治疗可以提高生存率,但患者的反应各不相同,而且由于
与疾病进展有关尚无确定的循环生物标志物可用于监测治疗反应。
患者内转移性肿瘤之间的分子异质性(肿瘤内异质性)和治疗-
受驱动的克隆进化使治疗的选择和安排复杂化,并限制了响应的持续时间。
无细胞血浆DNA(ctDNA)中癌症突变的循环水平与治疗密切相关
乳腺癌和结直肠癌的缓解和疾病进展。该项目的目标是评估
利用ctDNA为基础的血液测试治疗监测,并作为一种微创替代肿瘤复发,
转移性黑色素瘤患者的肿瘤基因分型活检。将通过分析来实现这一目标。
来自三个组群的转移性黑素瘤患者的系列血浆、肿瘤和种系样品:1)a
已完成的抗PD 1免疫治疗临床试验; 2)从Stand Up To Cancer前瞻性收集
黑色素瘤的基因组启用医学试验;和3)一项前瞻性观察性研究,
亚利桑那州马约诊所,采用标准护理免疫疗法和分子靶向药物治疗。
该提案的具体目的是:1)评估ctDNA作为监测生物标志物的临床验证
治疗反应; 2)评估ctDNA测序作为肿瘤活检的替代方法,以指导治疗
选择和3)鉴定对免疫疗法的获得性抗性的基因组驱动因素。对于目标1,患者-
将使用肿瘤外显子组测序鉴定特定突变,然后进行靶向数字测序,
定量ctDNA。治疗期间ctDNA水平的变化将与治疗期间的缓解和进展进行比较。
成像以评估临床有效性。对于目标2,将评估血浆和肿瘤样本的一致性
使用预处理血浆DNA的外显子组测序并与肿瘤外显子组测序进行比较。为
目的3,免疫治疗疾病进展时出现的新基因组改变将通过使用
治疗后血浆DNA的外显子组测序。获得性抗PD 1耐药性的基因组驱动因素
将通过评估疾病进展时反复改变的分子途径来鉴定抑制剂,
的cohort。
在该项目完成时,预计ctDNA分析在黑色素瘤中用于
肿瘤监测,作为肿瘤再活检的替代(和潜在改进),用于患者选择
并作为研究免疫治疗获得性耐药性的方法。
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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Muhammed Murtaza其他文献
Muhammed Murtaza的其他文献
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{{ truncateString('Muhammed Murtaza', 18)}}的其他基金
Treatment monitoring in early and locally advanced breast cancer using circulating tumor DNA analysis
使用循环肿瘤 DNA 分析监测早期和局部晚期乳腺癌的治疗
- 批准号:
10304444 - 财政年份:2020
- 资助金额:
$ 35.13万 - 项目类别:
Pre-analytical factors affecting ctDNA analysis in early and locally advanced breast cancer
影响早期和局部晚期乳腺癌 ctDNA 分析的分析前因素
- 批准号:
9893681 - 财政年份:2019
- 资助金额:
$ 35.13万 - 项目类别:
Pre-analytical factors affecting ctDNA analysis in early and locally advanced breast cancer
影响早期和局部晚期乳腺癌 ctDNA 分析的分析前因素
- 批准号:
10304711 - 财政年份:2019
- 资助金额:
$ 35.13万 - 项目类别:
Pre-analytical factors affecting ctDNA analysis in early and locally advanced breast cancer
影响早期和局部晚期乳腺癌 ctDNA 分析的分析前因素
- 批准号:
10246983 - 财政年份:2019
- 资助金额:
$ 35.13万 - 项目类别:
Pre-analytical factors affecting ctDNA analysis in early and locally advanced breast cancer
影响早期和局部晚期乳腺癌 ctDNA 分析的分析前因素
- 批准号:
10020370 - 财政年份:2019
- 资助金额:
$ 35.13万 - 项目类别:
Individualized monitoring of treatment response and resistance in patients with metastatic melanoma
转移性黑色素瘤患者治疗反应和耐药性的个体化监测
- 批准号:
9763501 - 财政年份:2018
- 资助金额:
$ 35.13万 - 项目类别:
Individualized monitoring of treatment response and resistance in patients with metastatic melanoma
转移性黑色素瘤患者治疗反应和耐药性的个体化监测
- 批准号:
10221639 - 财政年份:2018
- 资助金额:
$ 35.13万 - 项目类别:
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