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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：
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
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/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

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/文摘: