The Johns Hopkins Translational Science Team for the ET-CTN

约翰·霍普金斯大学 ET-CTN 转化科学团队

• 批准号: 10336134
• 负责人: Michael A Carducci
• 金额: $ 12.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10336134
• 关键词: Apoptosis; B lymphoid malignancy; BRAF gene; Cell Cycle Arrest; Cessation of life; Characteristics; Clinical Trials; Colorectal Cancer; Cytoplasm; Cytotoxic Chemotherapy; DNA Damage; Development; Early Therapeutic-Clinical Trials Network; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Fluorouracil; High-Frequency Microsatellite Instability; Immunoblotting; Immunotherapy; KRAS2 gene; Maintenance; Malignant Neoplasms; Messenger RNA; Microsatellite Instability; Microsatellite Repeats; Modeling; Molecular; Oncogenes; Oncogenic; Organoids; Patients; Probability; Prognosis; Refractory; Side; Signal Pathway; Stable Disease; Toxic effect; Translational Research; Translations; United States; Vascular Endothelial Growth Factors; bevacizumab; cancer type; capecitabine; chemotherapy; colon cancer patients; gain of function mutation; improved; inhibitor/antagonist; irinotecan; metastatic colorectal; mutant; mutational status; novel; overexpression; oxaliplatin; patient derived xenograft model; predicting response; response; screening; standard of care; transcriptome; treatment response; treatment strategy; tumor

Colorectal cancer (CRC) is a common and deadly condition. Worldwide, there are approximately 1.8 million new cases per year and 881,000 death per year, making it the third most prevalent and second most lethal cancer. In the Unites states alone, there were approximately 150,000 new cases and 53,000 deaths in 2020.2 It is estimated that by 2035 there may be 2.5 million new cases of CRC per year worldwide.3 While improved screening and treatments have lengthened survival, the 5-year survival probability of metastatic CRC (mCRC) is only about 12%. While immunotherapy is often effective in mCRC patients with microsatellite instability (MSI-H), patients with microsatellite stable (MSS) disease do not respond. In patients with microsatellite stable (MSS) mCRC, first- and second-line treatments are typically cytotoxic chemotherapy (combinations of oxaliplatin, irinotecan, fluorouracil, and capecitabine) with or without inhibitors of the epidermal growth factor receptor (EGFR, poor response if RAS/BRAF mutant or right-sided) and vascular endothelial growth factor (VEGF, bevacizumab). Novel treatment strategies for MSS mCRC are desperately needed, both in the maintenance and refractory settings. We hypothesize that selinexor in combination with DNA damaging chemotherapy (5- FU, capecitabine, and/or irinotecan) will synergize to generate DNA damage, cell cycle arrest, and apoptosis, producing promising anti-tumor efficacy in CRC patient-derived xenograft (PDX) models. Bevacizumab, when added to selinexor with or without chemotherapy, may also synergistically block VEGF signaling pathways, resulting in promising anti-tumor efficacy. We will characterize the efficacy, toxicity, mechanisms of action, and importance of KRAS mutational status to inform clinical trial development. In Aim 1, we will evaluate the response of selinexor as a single agent and in combination with DNA damaging agents and evaluate the anti- proliferative effects in patient-derived organoids (PDOs). Additionally, we use existing WES and whole transcriptome analysis to assess the molecular characteristics of the PDOs that determine response. In Aim 2, we will use the corresponding PDX models that responded in Aim 1 and assess the ability to predict response. Additionally, we will use IHC, and immunoblotting to determine the mechanism of response to these agents.

结直肠癌(CRC)是一种常见且致命的疾病。在世界范围内，大约有 每年新增180万例，每年死亡88.1万人，使其成为第三大最流行的 和第二致命的癌症。仅在美国，就有大约15万人 2020.2年度新增病例和53,000例死亡估计到2035年可能会新增250,000例 全世界每年的结直肠癌病例。3虽然改进的筛查和治疗延长了时间 生存，转移性结直肠癌(MCRC)的5年生存概率仅为12%左右。而当 免疫治疗对伴有微卫星不稳定性(MSI-H)的mCRC患者通常有效， 患有微卫星稳定型(MSS)病的患者没有反应。在携带微卫星的患者中 稳定的(MSS)mCRC，一线和二线治疗通常是细胞毒化疗 (奥沙利铂、伊立替康、氟尿嘧啶和卡培他滨的联合用药) 表皮生长因子受体(EGFR)的抑制剂，如果RAS/BRAF突变反应差 或右侧)和血管内皮生长因子(血管内皮生长因子，贝伐单抗)。新疗法 MSS mCRC的策略是迫切需要的，无论是在维护方面还是在耐火方面 设置。我们假设Selinexor联合DNA损伤化疗(5- 氟尿嘧啶、卡培他滨和/或伊立替康)将协同作用产生DNA损伤、细胞周期停滞、 和凋亡，在结直肠癌患者来源的异种移植(PDX)中产生良好的抗肿瘤效果 模特们。贝伐单抗在加入Selinexor时，无论是否进行化疗，也可能 协同阻断血管内皮生长因子信号通路，产生良好的抗肿瘤效果。我们 将描述KRAS的有效性、毒性、作用机制和重要性 突变状态为临床试验发展提供信息。在目标1中，我们将评估 Selinexor作为单药并与DNA损伤剂联合使用并评价其抗肿瘤作用 患者来源的有机化合物(PDO)的增殖效应。此外，我们使用现有的WE 和整个转录组分析，以评估PDO的分子特征 确定响应。在目标2中，我们将使用相应的PDX模型 目标1并评估预测反应的能力。此外，我们将使用IHC，以及 免疫印迹法以确定对这些药物的反应机制。