Project 2

项目2

• 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
• 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

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/摘要 SMARCA4突变的NSCLC代表了一种流行的、具有侵袭性的亚群，迫切需要有效的治疗。 SMARCA4编码BRG1，这是开关/蔗糖不可发酵(SWI/SNF)的关键ATPase亚基。 染色质重塑复合体。SMARCA4突变存在于9-11%的非小细胞肺癌患者中， 截断，BRG1失活突变包括超过三分之一的这些改变。因此，SMARCA4 是非小细胞肺癌中最常见的突变基因之一，没有针对性的治疗选择。SMARCA4 突变通常与降低敏感性的分子改变(Keap1和STK11突变)重叠 传统的治疗方法，如免疫治疗和化疗。在金研究所最近的一项研究中 实验室中，BRG1缺陷增加了DNA复制应激并增强了对ATR途径的敏感性 临床前肺癌模型中的抑制作用。共济失调延髓扩张症突变和RAD3相关(ATR)激酶是一种 细胞对复制应激反应的关键调节因子，激活DNA损伤检查点以响应 在切除DNA双链断裂过程中或由于DNA复制缺陷而产生的单链DNA。 在这里，我们将测试与BRG1缺陷相关的潜在复制应激提供 SMARCA4突变肺癌的治疗机会；我们将确定有效的药物组合 ATR抑制。我们将以我们的发现为基础，通过(目标1)全面描述 SMARCA4在非小细胞肺癌临床标本中的复制应激和免疫系统激活评估 突变，(目标2)评估SMARCA4突变NSCLC对复制应激靶向治疗的敏感性 缺陷，以及(目的3)进行临床前研究，以评估ATR抑制在 联合抗PD1/PD-L1免疫治疗。我们将利用SMARCA4现有的临床前模型- 在Kim Lab中产生的突变的BRG1缺失的NSCLC(CRISPR产生的BRG1缺失的等基因系， GEMM)和HATA实验室(BRG1缺陷患者来源的异种移植(PDX))，以及来自Dr. 评价Dagogo-Jack和程支持的合理候选药物组合的抗肿瘤活性 临床试验的未来发展。总体而言，这项拨款建议的研究旨在推进对病人的护理 通过探索一种利用独特漏洞的新颖、有前途的方法，与SMARCA4突变的NSCLC BRG1缺乏所致。我们预计，这项研究中提出的工作将为临床试验探索提供信息 新的联合治疗方法(ATR抑制加免疫治疗或吉西他滨)治疗慢性粒细胞白血病 BRG1缺陷的NSCLC，可能为未来的批准铺平道路。