Evaluation of BAY43-9006/Cetuximab in Colorectal Cancer

BAY43-9006/西妥昔单抗在结直肠癌中的评价

• 批准号: 7111870
• 负责人: WELLS A Messersmith
• 金额: $ 29.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-06 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111870
• 关键词: clinical research; colorectal neoplasms; irinotecan; lead; neoplasm /cancer; pharmacokinetics

DESCRIPTION (provided by applicant): Colorectal cancer will claim approximately 55,000 lives in the U.S. in 2005, and although recent advances have been improved survival incrementally, new treatment options and strategies are desperately needed. Cell signaling inhibitors have recently emerged as a successful anti-tumor strategy, and an antibody inhibitor of the EGFR pathway has made it to the colon cancer clinic. Another attractive target for anticancer drugs is the Ras/Raf/Mek/Erk signaling cascade, which promotes tumor cell growth, angiogenesis, and resistance to apoptosis. Mutations that constitutively activate the Ras oncogenic signaling pathway are highly prevalent in colorectal cancer (50-70%). In addition, the Ras pathway is part of the signaling network for EGFR, which is a validated target in colorectal cancer. One major obstacle to the development of signal transduction inhibitors is cross-talk between signaling pathways, which can subvert the effects of a given inhibitor. Our laboratory has found that combinations of inhibitors may overcome this challenge, where a cell line xenograft that is resistant to an EGFR or Erk inhibitor alone becomes sensitive when the two are combined. BAY 43-9006 is a novel oral Raf kinase inhibitor with inhibitory activity against VEGFR and PDGFR as well. We hypothesize that combining BAY 43-9006 with the standard treatment for chemoresistant advanced colorectal cancer (irinotecan/cetuximab) will result in synergistic antitumor effects. The goal is to complete a phase I/I I clinical, pharmacological, and biological study of BAY 43-9006 in combination with cetuximab and irinotecan in patients with advanced colorectal cancer. Utilizing a lead-in design of BAY 43-9006 with cetuximab, combined with pre- and post treatment tumor and normal tissue samples, the biological effects of this combination will be fully characterized. Phamacokinetic and pharmacodynamic studies of this combination will represent the foundation and rationale for further studies.

描述（由申请人提供）：大肠癌将在2005年在美国夺去约55,000人的生命，尽管最近的进步逐渐改善，但迫切需要新的治疗选择和策略。细胞信号抑制剂最近已成为成功的抗肿瘤策略，EGFR途径的抗体抑制剂已成为结肠癌诊所。抗癌药物的另一个有吸引力的靶标是RAS/RAF/MEK/ERK信号级联，该级联促进了肿瘤细胞的生长，血管生成和对凋亡的抗性。组成性激活RAS致癌信号通路的突变在大肠癌中非常普遍（50-70％）。此外，RAS途径是EGFR信号网络的一部分，EGFR是结直肠癌的验证靶标。信号转导抑制剂发展的一个主要障碍是信号通路之间的串扰，这可以颠覆给定的抑制剂的影响。我们的实验室发现，抑制剂的组合可能会克服这一挑战，在这种挑战中，仅当两者组合时，对EGFR或ERK抑制剂具有抗药性的细胞系异种移植物变得敏感。 BAY 43-9006是一种新型的口服RAF激酶抑制剂，对VEGFR和PDGFR也具有抑制作用。我们假设将Bay 43-9006与化学抗性晚结直肠癌（Irinotecan/cetuximab）的标准治疗相结合将导致协同抗肿瘤作用。目的是在患有晚期结直肠癌的患者中完成I/I I期临床，药理和生物学研究，并结合Cetuximab和irinotecan结合使用。通过使用西妥昔单抗的43-9006海湾设计，结合了治疗前和治疗后的肿瘤和正常组织样品，该组合的生物学作用将得到充分表征。该组合的Phamacokinetic和药效学研究将代表进一步研究的基础和基本原理。