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：
10221639
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221639
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 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.

项目概要/摘要：转移性黑色素瘤是一种致命性疾病，五年生存率仅为 20%。免疫疗法和分子疗法有针对性的治疗可提高生存率，但不同患者的反应各不相同，而且获益往往是暂时的到疾病进展。目前还没有确定的循环生物标志物来监测治疗反应。患者体内转移性肿瘤之间的分子异质性（肿瘤内异质性）和治疗- 驱动的克隆进化使治疗的选择和安排变得复杂，并限制了反应的持续时间。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反应和疾病进展。该项目的目标是评估基于 ctDNA 的血液检测可用于治疗监测并作为肿瘤再治疗的微创替代方案转移性黑色素瘤患者的肿瘤基因分型活组织检查。这一目标将通过分析来实现来自三个队列的转移性黑色素瘤患者的系列血浆、肿瘤和种系样本：1) 完成抗PD1免疫疗法的临床试验； 2) 来自 Stand Up To Cancer 的前瞻性收藏黑色素瘤基因组医学试验； 3）对患者进行的前瞻性观察研究亚利桑那州梅奥诊所，采用标准护理免疫疗法和分子靶向药物进行治疗。该提案的具体目标是 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来指导治疗选择和3）确定免疫治疗获得性耐药的基因组驱动因素。对于目标 1，患者- 将使用肿瘤外显子组测序来识别特定突变，然后进行有针对性的数字测序量化 ctDNA。治疗期间 ctDNA 水平的变化将与治疗期间的反应和进展进行比较影像学评估临床有效性。对于目标 2，将评估血浆和肿瘤样本的一致性使用治疗前血浆 DNA 的外显子组测序并与肿瘤外显子组测序进行比较。为了目标 3，免疫治疗疾病进展时出现的新基因组改变将通过以下方法识别：治疗后血浆 DNA 的外显子组测序。抗 PD1 获得性耐药的基因组驱动因素将通过评估在疾病进展过程中反复改变的分子途径来识别抑制剂队列。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，作为患者选择的肿瘤再活检的替代方案（和潜在的改进）并将建立一种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（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-wide analysis of aberrant position and sequence of plasma DNA fragment ends in patients with cancer.

对癌症患者血浆 DNA 片段末端的异常位置和序列进行全基因组分析。

DOI：
发表时间：
2023-01-11
期刊：
影响因子：
17.1
作者：
Budhraja, Karan K;McDonald, Bradon R;Stephens, Michelle D;Contente;Markus, Havell;Farooq, Maria;Favaro, Patricia F;Connor, Sydney;Byron, Sara A;Egan, Jan B;Ernst, Brenda;McDaniel, Timothy K;Sekulic, Aleksandar;Tran, Nhan L;Prado
通讯作者：
Prado

Analysis of recurrently protected genomic regions in cell-free DNA found in urine.

对尿液中发现的无细胞 DNA 中反复受保护的基因组区域进行分析。

DOI：
发表时间：
2021
期刊：
影响因子：
17.1
作者：
Markus, Havell;Zhao, Jun;Contente;Stephens, Michelle D;Raupach, Elizabeth;Odenheimer;Connor, Sydney;McDonald, Bradon R;Moore, Bethine;Hutchins, Elizabeth;McGilvrey, Marissa;de la Maza, Michelina C;Van Keuren
通讯作者：
Van Keuren

On the stem cell origin of cancer.

关于癌症的干细胞起源。