Evaluation of BAY43-9006/Cetuximab in Colorectal Cancer

描述（由申请人提供）：2005年，结直肠癌将在美国夺去大约55,000人的生命，尽管最近的进展已经逐步提高了生存率，但迫切需要新的治疗方案和策略。细胞信号抑制剂最近作为一种成功的抗肿瘤策略出现，EGFR途径的抗体抑制剂已经进入结肠癌临床。另一个吸引人的抗癌药物靶点是Ras/Raf/Mek/Erk信号级联，它促进肿瘤细胞生长、血管生成和对凋亡的抵抗。组成性激活Ras致癌信号通路的突变在结直肠癌中非常普遍（50-70%）。此外，Ras通路是EGFR信号网络的一部分，EGFR是结直肠癌的有效靶点。发展信号转导抑制剂的一个主要障碍是信号通路之间的串扰，这可能会破坏给定抑制剂的作用。我们的实验室已经发现，抑制剂的组合可以克服这一挑战，其中对单独的EGFR或Erk抑制剂具有抗性的细胞系异种移植物在两者结合时变得敏感。BAY 43-9006是一种新型的口服Raf激酶抑制剂，对VEGFR和PDGFR具有抑制活性。我们假设BAY 43-9006联合化疗耐药晚期结直肠癌的标准治疗（伊立替康/西妥昔单抗）将产生协同抗肿瘤作用。目标是完成BAY 43-9006联合西妥昔单抗和伊立替康治疗晚期结直肠癌患者的I/I期临床、药理学和生物学研究。采用BAY 43-9006联合西妥昔单抗的导入设计，结合治疗前后的肿瘤和正常组织样本，充分表征该组合的生物学效应。该组合的药代动力学和药效学研究将为进一步研究奠定基础和理论基础。

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.