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
• 负责人: Muhammed Murtaza
• 金额: $ 40.29万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9763501
• 关键词: Address; Affect; Aftercare; Arizona; Automobile Driving; BRAF gene; Biological Markers; Biopsy; Blood Circulation; Blood Tests; Blood specimen; Cells; Clinic; Clinical; Clinical Trials; Clonal Evolution; Collection; Colorectal Cancer; DNA; DNA Sequence Alteration; DNA analysis; DNA sequencing; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disseminated Malignant Neoplasm; Drug resistance; Enrollment; Genes; Genomics; Genotype; Goals; Heterogeneity; Image; Immune system; Immunotherapy; JAK1 gene; JAK2 gene; MEKs; Malignant Neoplasms; Measures; Medicine; Metastatic Melanoma; Methods; Molecular; Molecular Target; Monitor; Mutation; Neoplasm Metastasis; Observational Study; PD-1 inhibitors; Pathway interactions; Patient Selection; Patients; Plasma; Prediction of Response to Therapy; Predictive Value; Privatization; Progression-Free Survivals; Recurrence; Resistance; Resistance development; Resolution; Sampling; Selection for Treatments; Somatic Mutation; Stable Disease; Surrogate Endpoint; Testing; TimeLine; Tissues; Treatment Protocols; Validation; acquired treatment resistance; actionable mutation; anti-PD-1; base; circulating biomarkers; clinical development; cohort; digital; effective therapy; exome; exome sequencing; follow-up; founder mutation; improved; improved outcome; inhibitor/antagonist; longitudinal analysis; malignant breast neoplasm; melanoma; melanoma biomarkers; minimally invasive; molecular drug target; molecular targeted therapies; mutant; neoantigens; partial response; prospective; recruit; response; standard of care; targeted treatment; therapy resistant; tool; treatment response; tumor; tumor DNA; tumor heterogeneity; unnecessary treatment

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.

项目摘要/摘要： 转移性黑色素瘤是一种致命疾病，五年生存率为20％。免疫疗法和分子 有针对性的治疗提高了生存 疾病进展。没有建立的循环生物标志物来监测治疗反应。 患者内转移性肿瘤（肿瘤内异质性）与治疗 - 驱动的克隆进化使选择和计划的治疗时间变得复杂，并限制了响应持续时间。 无细胞血浆DNA（CTDNA）中癌症突变的循环水平与处理密切相关 乳腺癌和大肠癌的反应和疾病进展。该项目的目的是评估 基于CTDNA的血液测试用于治疗监测，并作为肿瘤重新侵入的替代品 转移性黑色素瘤患者的肿瘤基因分型活检。该目标将通过分析实现 来自三个队列的转移性黑色素瘤患者的连续血浆，肿瘤和种系样品：1）a 抗PD1免疫疗法完成了临床试验； 2）从站立到癌症的前瞻性收集 基因组启用黑色素瘤试验的药物； 3）对患者的前瞻性观察研究 亚利桑那州梅奥诊所（Mayo Clinic Arizona），使用护理标准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作为监测的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案来指导治疗 选择和3）确定获得免疫疗法耐药性的基因组驱动因素。对于AIM 1，患者 - 将使用肿瘤外部测序确定特定突变，然后进行针对性的数字测序 量化ctDNA。将治疗过程中ctDNA水平的变化与反应和进展 成像以评估临床有效性。对于AIM 2，将评估血浆和肿瘤样品的一致性 使用前处理血浆DNA的外显子组测序与肿瘤外显子组测序的比较。为了 AIM 3，将使用免疫疗法的疾病进展产生的新基因组改变。 处理后血浆DNA的外显子组测序。获得抗PD1的基因组驱动因素 抑制剂将通过评估跨疾病进展时反复改变的分子途径来确定抑制剂 队列。 该项目完成后，预计CTDNA分析在黑色素瘤中的有用程度 肿瘤监测，作为对患者选择的肿瘤重生（潜在改善）的替代方法 作为研究获得的免疫疗法抗性的一种方法，将建立。