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Identification of genomic drivers of brain metastases in lung adenocarcinoma

肺腺癌脑转移基因组驱动因素的鉴定

基本信息

批准号：
10400649
负责人：
Priscilla Kaliopi Brastianos
金额：
$ 69.55万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2018-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400649
关键词：
Biological Assay Biological Process Cancer cell line Cells Clinical Clinical Trials Clonal Evolution Collaborations Collection Common Neoplasm Complex Complication Computer Analysis Credentialing Critical Pathways DNA Sequence Alteration DNA sequencing Data Data Set Development Diagnosis Disease Encyclopedias Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Evolution Gene Expression Generations Genes Genomics Goals Histology Immunotherapy In Vitro Individual International Knowledge Lesion Lung Adenocarcinoma Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Metastatic Neoplasm to the Central Nervous System Metastatic malignant neoplasm to brain Metastatic to Methods Mission Modeling Molecular Mus Mutate Mutation Neoplasm Metastasis Newly Diagnosed Nonmetastatic Normal tissue morphology Pathway interactions Patients Phase Phenotype Phylogenetic Analysis Primary Neoplasm Public Health Recurrence Reporting Role Sampling Somatic Mutation Systemic Therapy Techniques Testing The Cancer Genome Atlas Therapeutic Therapeutic Intervention Tissue Banks Tissue Sample Translations Trees Tumor Tissue United States National Institutes of Health Xenograft Model analysis pipeline base burden of illness cancer complication cancer type chemotherapy clinically actionable cohort data archive design driver mutation effective therapy exome sequencing experience gene function genome-wide in vivo innovation insight loss of function metastatic process migration molecular marker next generation sequencing novel novel therapeutics patient derived xenograft model predicting response predictive marker prevent sample collection success targeted treatment therapeutic candidate therapeutic target therapy resistant

项目摘要

Project Summary Fifty percent of patients with lung adenocarcinoma will develop brain metastases. Patients frequently develop brain metastasis even while their extracranial disease remains under control. Unfortunately, treatment options are limited, and most current clinical trials in the US exclude patients with brain metastases. Our limited understanding of the molecular drivers of brain metastases has hampered the development of novel therapeutics for this common complication of cancer. Our group recently completed whole-exome sequencing of 104 brain metastases, primary tumors and normal tissue across many histologies. In this initial dataset, which included only 29 brain metastases from lung adenocarcinoma, we detected clinically actionable alterations that were unique to the brain metastases. We have now assembled a large cohort of lung adenocarcinoma brain metastases. Our proposed genomic analysis will focus on identifying and characterizing the molecular alterations in brain metastases from lung adenocarcinoma. We will analyze brain metastases and primary lung tumors and compare to lung cancers that do not metastasize. We will characterize these alterations using in vitro and in vivo assays of metastasis, including patient derived xenograft models. Identification of these mutations will aid in the design of more effective treatments for brain metastases.

项目摘要 50%的肺腺癌患者会发生脑转移。患者经常发生脑转移，即使他们的颅外疾病仍在控制之中。不幸的是，治疗方案有限，目前大多数美国的临床试验排除了脑转移患者。我们有限的理解脑转移的分子驱动因素阻碍了新的治疗这种常见的癌症并发症。我们的团队最近完成了104例脑转移瘤的全外显子组测序，原发性肿瘤和许多组织学中的正常组织。在这个初始数据集中，仅包括29例肺腺癌脑转移瘤，我们检测了临床脑转移瘤特有的可操作的改变。我们现在已经聚集了一个肺腺癌脑转移的大型队列。我们提出的基因组分析将集中在识别和表征的分子改变，肺腺癌脑转移我们会分析脑转移，原发性肺肿瘤，并与未转移的肺癌进行比较。我们将使用体外和体内转移测定来表征这些改变，包括患者来源的异种移植物模型。这些突变的鉴定将有助于设计更有效的治疗脑转移的方法

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA-Mutant Breast Cancer Brain Metastases

DOI：
10.1158/1078-0432.ccr-18-3049
发表时间：
2019-06-01
期刊：
CLINICAL CANCER RESEARCH
影响因子：
11.5
作者：
Ippen, Franziska M.;Alvarez-Breckenridge, Christopher A.;Brastianos, Priscilla K.
通讯作者：
Brastianos, Priscilla K.

Preclinical Solid Tumor Models to Study Novel Therapeutics in Brain Metastases.

DOI：
10.1002/cpz1.284
发表时间：
2021-11
期刊：
Current protocols
影响因子：
0
作者：
Singh M;Dahal A;Brastianos PK
通讯作者：
Brastianos PK

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.

DOI：
10.1158/1078-0432.ccr-22-0383
发表时间：
2022-08-02
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
通讯作者：

The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.

ERK 抑制剂 LY3214996 可增强 BRAFV600E 黑色素瘤脑转移临床前小鼠模型中的抗 PD-1 免疫治疗。

DOI：
10.1093/neuonc/noad248
发表时间：
2024
期刊：
Neuro-oncology
影响因子：
15.9
作者：
deSauvage,MagaliA;Torrini,Consuelo;Nieblas-Bedolla,Edwin;Summers,ElizabethJ;Sullivan,Emily;Zhang,BritneyS;Batchelor,Emily;Marion,Braxton;Yamazawa,Erika;Markson,SamuelC;Wakimoto,Hiroaki;Nayyar,Naema;Brastianos,PriscillaK
通讯作者：
Brastianos,PriscillaK