权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

PROJECT 3: Applying Liquid Biopsy Technologies to Detect Clinical Response and Mechanisms of Resistance in the Treatment of LMS

项目 3：应用液体活检技术检测 LMS 治疗的临床反应和耐药机制

基本信息

批准号：
10705742
负责人：
Brian Crompton
金额：
$ 54.15万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705742
关键词：
Adult Anesthesia procedures Biological Markers Biology Biopsy Biopsy Specimen Blood Blood specimen Cancer Biology Chemoresistance Chemotherapy-Oncologic Procedure Clinical Clinical Research Clinical Trials Clonal Evolution Collection Consensus Correlation Studies Cytotoxic Chemotherapy Data Detection Development Diagnosis Diagnostic Disease Disease Progression Disease Resistance Doxorubicin Evolution Future Gene Mutation Genetic Genomics Heterogeneity Image In Vitro Lesion Malignant Neoplasms Metastatic Leiomyosarcoma Modality Modeling Mutation Newly Diagnosed Oncologist Operative Surgical Procedures Outcome Patient Selection Patient-Focused Outcomes Patients Pattern Pilot Projects Plasma Prognosis Prognostic Factor Prognostic Marker Progression-Free Survivals Proxy Radiology Specialty Recurrence Regimen Relapse Research Research Personnel Resistance Risk Safety Sampling Single Nucleotide Polymorphism Smooth Muscle Soft tissue sarcoma Solid Systemic Therapy Technology Testing Time Toxic effect Treatment Failure Treatment Futility Unresectable Validation Variant burden of illness chemotherapy clinical care clinical decision-making cohort deep sequencing design disease natural history disorder control docetaxel experience experimental study gemcitabine genomic profiles high risk improved improved outcome in vivo insight leiomyosarcoma liquid biopsy next generation sequencing novel novel strategies novel therapeutic intervention participant enrollment patient derived xenograft model patient subsets personalized medicine prevent prognostic prospective radiation risk radiological imaging resistance mechanism response side effect single cell sequencing therapy resistant treatment response treatment strategy tumor tumor DNA tumor heterogeneity tumor progression

项目摘要

Project 3: Project Summary / Abstract Leiomyosarcoma (LMS) is an aggressive soft tissue sarcoma (STS) with evidence of smooth muscle differentiation and is one of the most common STS in adults. Nearly half of patients will develop metastatic disease either prior to diagnosis or during their clinical care. Chemotherapy is the primary modality for treatment of metastatic LMS, and the standard chemotherapy regimens use doxorubicin or gemcitabine. These chemotherapy agents carry a significant risk of toxicity, yet only 15-20% of patients will experience an objective response and only 5-10% will achieve long-term disease control. The median progression-free survival for patients with metastatic LMS treated with either doxorubicin or a gemcitabine-based regimen is 6 months. Despite intensive research efforts to understand the biology of LMS, most studies have been underpowered to correlate recurrent genomic features at diagnosis with clinical outcomes. Patterns of tumor evolution that give rise to relapse and chemotherapy resistance have remained unstudied due to the safety concerns associated with anesthesia and surgery to obtain serial tumor biopsies for research. Newly available liquid biopsy technologies enable the detection of circulating tumor DNA (ctDNA) in the blood of patients with cancer. In some malignancies, ctDNA levels correlate with prognosis, and changes in ctDNA levels correspond to disease response and progression. In Project 3, a prospective collection of blood samples from patients with metastatic LMS receiving doxorubicin or gemcitabine/docetaxel chemotherapy will be used to study the correlation between ctDNA levels and clinical outcomes in patients with newly diagnosed metastatic LMS as Aim 1. Data from the biomarker study will also validate ctDNA as a novel prognostic biomarker. Copy number alterations of genes in LMS from patients enrolled in the biomarker study in Aim 1 will also be examined as potential prognostic factors and biomarkers of resistance to front-line chemotherapy. Recent studies show that deep sequencing of ctDNA can be used as a proxy for sequencing of tumor biopsy samples. Evidence suggests that genomic profiles from ctDNA better represent genomic heterogeneity in patients with metastatic disease than any single biopsy sample. In Aim 2, we propose to profile serial ctDNA samples to identify recurrent patterns of tumor heterogeneity and disease evolution in LMS, and to validate identified acquired genetic changes associated with chemotherapy resistance using patient-derived xenograft models. These studies will have a major impact on development of a biomarker for LMS and LMS treatment and will fundamentally broaden the understanding of LMS and the natural history of this disease. Validation of mechanisms of evolution that give rise to resistant disease could lead to development of novel therapeutic approaches designed to prevent the emergence of resistance and improve outcomes for patients with metastatic LMS in the near future.

项目3：项目摘要/摘要