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 每年新增病例 180 万，死亡人数 881,000，使其成为第三大流行病 和第二大致命癌症。仅在美国各州就有大约 150,000 2020 年新增病例和死亡 53,000 例。2 预计到 2035 年可能新增 250 万例 全球每年都有 CRC 病例。3 虽然筛查和治疗得到了改善，但延长了 生存率方面，转移性结直肠癌（mCRC）的5年生存率仅为12%左右。尽管 免疫疗法对于微卫星不稳定（MSI-H）的转移性结直肠癌患者通常有效， 患有微卫星稳定（MSS）疾病的患者没有反应。患有微卫星的患者 稳定（MSS）转移性结直肠癌，一线和二线治疗通常是细胞毒性化疗 （奥沙利铂、伊立替康、氟尿嘧啶和卡培他滨的组合）有或没有 表皮生长因子受体抑制剂（EGFR，如果 RAS/BRAF 突变，反应较差 或右侧）和血管内皮生长因子（VEGF、贝伐珠单抗）。新颖的治疗方法 迫切需要针对 MSS mCRC 的维持策略和难治性策略 设置。我们假设 selinexor 与 DNA 损伤化疗联合使用 (5- FU、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、 和细胞凋亡，在 CRC 患者来源的异种移植物 (PDX) 中产生有希望的抗肿瘤功效 模型。贝伐单抗在联合或不联合化疗的情况下添加到 selinexor 中时，也可能 协同阻断 VEGF 信号通路，从而产生有希望的抗肿瘤功效。我们 将描述 KRAS 的功效、毒性、作用机制和重要性 突变状态为临床试验开发提供信息。在目标 1 中，我们将评估 selinexor 作为单一药物并与 DNA 损伤剂联合使用并评估抗- 患者来源的类器官（PDO）的增殖作用。此外，我们使用现有的 WES 和全转录组分析来评估 PDO 的分子特征 确定响应。在目标 2 中，我们将使用响应中的相应 PDX 模型 目标 1 并评估预测反应的能力。此外，我们将使用 IHC，并且 免疫印迹以确定对这些药物的反应机制。