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 1.8每年有100万新病例和88.1万人死亡，使其成为第三大流行病 也是第二致命的癌症仅在美国，就有大约15万人 2020年新增病例和53，000例死亡。2据估计，到2035年， 尽管筛查和治疗的改善延长了 在生存率方面，转移性CRC（mCRC）的5年生存概率仅为约12%。而 免疫疗法通常对具有微卫星不稳定性（MSI-H）的mCRC患者有效， 患有微卫星稳定（MSS）疾病的患者没有反应。在微卫星 稳定（MSS）mCRC，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联合用药），伴或不伴 表皮生长因子受体（EGFR）抑制剂，如果RAS/BRAF突变，则疗效差 或右侧）和血管内皮生长因子（VEGF，贝伐单抗）。新型治疗 无论是在维持性还是难治性，都迫切需要MSS mCRC的策略 设置.我们假设赛林克斯联合DNA损伤化疗（5- 100 mg/kg）， FU、卡培他滨和/或伊立替康）将协同产生DNA损伤、细胞周期阻滞， 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疗效 模型贝伐珠单抗，当加入到赛林克斯与或不与化疗，也可能 协同阻断VEGF信号通路，产生有希望的抗肿瘤功效。我们 将描述KRAS的疗效、毒性、作用机制和重要性 突变状态以告知临床试验开发。在目标1中，我们将评估 selinexor作为单一药剂和与DNA损伤剂组合，并评估抗- 患者源性类器官（PDO）的增殖效应。此外，我们使用现有的WES 和全转录组分析，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， 免疫印迹以确定对这些试剂的应答机制。