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

Project 2

项目2

基本信息

批准号：
10673932
负责人：
David A Barbie
金额：
$ 37.98万
依托单位：
DANA-FARBER CANCER INST
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：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673932
关键词：
ATP phosphohydrolase Ataxia Biopsy CD8-Positive T-Lymphocytes CHEK1 gene Cancer Center Cancer Model Cancer Therapy Evaluation Program Cell Line Cessation of life Chromatin Remodeling Factor Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Cyclic GMP Cytotoxic T-Lymphocytes DNA DNA Damage DNA Double Strand Break DNA biosynthesis DNA damage checkpoint Defect Drug Combinations Excision Future Gamma-H2AX Gene Expression Genes Genetically Engineered Mouse Genomic Instability Genotype Goals Grant Human Immune system Immunofluorescence Immunologic Immunohistochemistry Immunologic Markers Immunotherapy Individual Innate Immune Response Laboratories Lymphocytic Infiltrate Malignant Neoplasms Malignant neoplasm of lung Mediating Modality Modeling Molecular Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Outcome PD-1/PD-L1 PDL1 inhibitors Pathway interactions Patient Care Patients Phosphotransferases Pre-Clinical Model Prognosis Proteins Ribonucleotide Reductase SMARCA4 gene STK11 gene Sampling Single-Stranded DNA Specimen Stimulator of Interferon Genes Stress Sucrose System T cell infiltration Testing Therapeutic Topoisomerase Inhibitors Tumor-infiltrating immune cells United States Work Xenograft procedure anti-PD-1 antitumor effect biological adaptation to stress biomarker identification chemotherapeutic agent chemotherapy clinical development drug candidate effective therapy experimental study gemcitabine hydroxyurea immune checkpoint blockade immunoregulation improved inhibitor innovation loss of function mutant novel p53-binding protein 1 patient derived xenograft model patient prognosis phase 1 study pre-clinical precision medicine preclinical study prevent programmed cell death ligand 1 programmed cell death protein 1 protein expression replication stress response targeted treatment therapeutic target treatment response tumor

项目摘要

Summary/Abstract SMARCA4-mutant NSCLC represents a prevalent, aggressive subset in urgent need of effective therapies. SMARCA4 encodes BRG1, a key ATPase subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. SMARCA4 mutations are present in 9-11% of patients with NSCLC, with truncating, BRG1-inactivating mutations comprising greater than one-third of these alterations. Thus, SMARCA4 is one of the most frequently mutated genes in NSCLC that has no targeted treatment option. SMARCA4 mutations often overlap with molecular alterations (KEAP1 and STK11 mutations) that decrease sensitivity to traditional therapeutic approaches such as immunotherapy and chemotherapy. In a recent study from the Kim laboratory, BRG1 deficiency increased DNA replicative stress and enhanced sensitivity to ATR pathway inhibition in preclinical lung cancer models. Ataxia telangectasia mutated and Rad3-related (ATR) kinase is a key regulator of cellular response to replication stress that activates the DNA damage checkpoint in response to single strand DNA created during the resection of DNA double-strand breaks or due to defects in DNA replication. Here, we will test the hypothesis that the underlying replication stress associated with BRG1 deficiency provides a therapeutic opportunity for SMARCA4 mutant lung cancer; we will identify drug combinations effective with ATR inhibition. We will build upon our discoveries by (Aim 1) comprehensively characterizing hallmarks of replication stress and assessing immune system activation in NSCLC clinical specimens with SMARCA4 mutations, (Aim 2) evaluating sensitivity of SMARCA4-mutant NSCLCs to therapies targeting replication stress defects, and (Aim 3) performing pre-clinical studies to assess the anti-tumor effects of ATR inhibition in combination with anti-PD1/PD-L1 immunotherapy. We will leverage existing preclinical models of SMARCA4- mutant, BRG1-deficient NSCLC generated in the Kim Lab (CRISPR-generated isogenic BRG1-deficient lines, GEMM) and Hata Lab (BRG1-deficient patient-derived xenograft (PDX)), together with patient samples from Drs. Dagogo-Jack and Cheng to evaluate the antitumor activity of rational combinations of candidate drugs to support future development of clinical trials. Overall, the studies proposed in this grant aim to advance the care of patients with SMARCA4-mutant NSCLC by exploring a novel, promising approach that exploits a unique vulnerability induced by BRG1 deficiency. We envision that the work proposed in this study will inform clinical trials exploring novel combination therapy approaches (ATR inhibition plus immunotherapy or gemcitabine) in patients with BRG1-deficient NSCLC, potentially paving the way for future approvals.

摘要/文摘