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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：
Muhammed Murtaza
金额：
$ 35.13万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
https://reporter.nih.gov/project-details/10304535
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 exome tumor heterogeneity unnecessary 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。