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）：胰腺癌是一种统一的致命疾病，迫切需要基于机制的疗法来改善生存率，尤其是在转移性，无法使用的肿瘤患者中。在大多数胰腺癌细胞系中可以看到刺猬（HH）途径激活，并且可以通过HH小分子拮抗剂cyclopamine极大地抑制体外生长。提出了对胰腺癌中HH抑制剂的综合临床前分析，它使用体内模型概括了人类胰腺癌进展的复杂性。已经从切除的人类胰腺癌中建立了低音细胞系，并将用于在小没有小鼠的胰腺中产生正性异种移植物。 环主要或口服可生物利用的合成HH抑制剂（Genentech，Inc。）将作为单一疗法进行28天。治疗疗效与对照小鼠将通过客观的总和组织病理学参数（包括开发腹腔内转移）以及生存分析来评估死灵的治疗效率与对照小鼠。 HH拮抗剂与抗代谢物（吉西他滨）之间的协同作用将在异种移植癌的子集中进行评估。胰腺内肿瘤和侵入性胰腺癌的转基因小鼠模型已通过胰腺中的致癌性KRAS的misexpression发展。将在该模型中研究HH信号传导的作用，包括在多阶段发展为侵入性癌症过程中抑制途径的作用。作为临床试验的序幕，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确定的全局表达曲线相关联的生物标志物，在50个胰腺癌细胞系的小组中使用寡核苷酸微阵列确定的全局表达曲线来定义。基于HH抑制剂在临床前研究中的疗效以及对反应的预测生物标志物的鉴定，使用可切除的胰腺癌患者使用口服可生物可利用的合成HH抑制剂进行了II期临床试验。