Hedgehog Inhibitors in Pancreas Cancer

胰腺癌中的 Hedgehog 抑制剂

• 批准号: 6905124
• 负责人: ANIRBAN MAITRA
• 金额: $ 32.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905124
• 关键词: adenocarcinoma; antineoplastics; athymic mouse; biological signal transduction; biomarker; carcinogenesis inhibitor; gemcitabine; gene expression profiling; genetically modified animals; human tissue; metastasis; microarray technology; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; pancreas neoplasms; pathologic process; transcription factor; xenotransplantation

DESCRIPTION (provided by applicant): Pancreatic cancer is a uniformly lethal disease, and there is an urgent need for potent, mechanism-based therapies to improve survival, especially in patients with metastatic, inoperable tumors. Hedgehog (Hh) pathway activation is seen in the majority of pancreatic cancer cell lines, and in vitro growth can be profoundly inhibited by the Hh small molecule antagonist cyclopamine. A comprehensive preclinical analysis of Hh inhibitors in pancreatic cancer is proposed, using in vivo models that recapitulate the complexities of human pancreatic cancer progression. Low-passage cell lines have been established from resected human pancreatic cancers, and will be used for generating orthotropic xenografts in pancreata of athymic mice. Either cyclopamine or an orally bioavailable synthetic Hh inhibitor (Genentech, Inc.) will be administered as monotherapy for 28 days. Treatment efficacy versus control mice will be assessed at necropsy by objective gross and histopathologic parameters, including development of intra-abdominal metastases, and by survival analysis. Synergism between the Hh antagonists and an anti-metabolite (gemcitabine) will be assessed in a subset of xenografted cancers. A transgenic mouse model of pancreatic intraepithelial neoplasia and invasive pancreatic cancer has been developed by misexpression of oncogenic KRAS in the pancreas. The role of Hh signaling, including effects of inhibiting pathway during the multistage progression to invasive cancer, will be studied in this model. As a prelude to clinical trials, biomarkers that predict responsiveness to Hh antagonists will be defined by correlating in vitro therapeutic response with the expression of Hh pathway genes and to global expression profiles determined using oligonucleotide microarrays, in a panel of 50 pancreatic cancer cell lines. Based on the efficacy of Hh inhibitors in the preclinical studies and the identification of predictive biomarkers for response, Phase II clinical trials will be initiated in patients with unresectable pancreatic cancers using the orally bioavailable synthetic Hh inhibitors.

描述（由申请人提供）：胰腺癌是一种均致死的疾病，迫切需要有效的、基于机制的疗法来提高生存率，特别是对于患有转移性、无法手术的肿瘤的患者。 Hedgehog (Hh) 通路激活存在于大多数胰腺癌细胞系中，并且 Hh 小分子拮抗剂环杷明可以深度抑制体外生长。提出使用概括人类胰腺癌进展复杂性的体内模型，对胰腺癌中的 Hh 抑制剂进行全面的临床前分析。已经从切除的人胰腺癌中建立了低传代细胞系，并将用于在无胸腺小鼠的胰腺中产生正交异种移植物。 环巴明或口服生物可利用的合成 Hh 抑制剂（Genentech, Inc.）将作为单一疗法施用 28 天。与对照小鼠相比的治疗效果将在尸检时通过客观的总体和组织病理学参数（包括腹内转移的发展）以及通过生存分析来评估。 Hh 拮抗剂和抗代谢物（吉西他滨）之间的协同作用将在异种移植癌症的子集中进行评估。通过胰腺中致癌 KRAS 的错误表达，建立了胰腺上皮内瘤变和侵袭性胰腺癌的转基因小鼠模型。将在该模型中研究 Hh 信号传导的作用，包括在侵袭性癌症的多阶段进展过程中抑制途径的作用。作为临床试验的前奏，预测对 Hh 拮抗剂反应的生物标志物将通过将体外治疗反应与 Hh 途径基因的表达以及使用寡核苷酸微阵列在一组 50 个胰腺癌细胞系中确定的整体表达谱相关联来定义。基于 Hh 抑制剂在临床前研究中的功效以及预测反应生物标志物的鉴定，将在不可切除的胰腺癌患者中启动使用口服生物可利用的合成 Hh 抑制剂的 II 期临床试验。