Hedgehog Inhibitors in Pancreas Cancer

描述（由申请人提供）：胰腺癌是一种普遍致命的疾病，迫切需要有效的、基于机制的治疗来提高生存率，特别是对于转移性、不能手术的肿瘤患者。在大多数胰腺癌细胞系中可以看到Hedgehog （Hh）通路的激活，并且Hh小分子拮抗剂环巴胺可以深度抑制体外生长。提出了一项全面的临床前分析Hh抑制剂在胰腺癌中，使用体内模型，概括了人类胰腺癌进展的复杂性。从切除的人类胰腺癌中建立了低传代细胞系，并将用于在胸腺小鼠胰腺中产生正交异性异种移植物。环巴胺或口服生物可利用的合成Hh抑制剂（Genentech, Inc.）将作为单药治疗28天。与对照组相比，治疗效果将在尸检时通过客观的大体和组织病理学参数（包括腹腔内转移的发展）和生存分析来评估。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一个亚群中进行评估。通过胰腺中致癌基因KRAS的错误表达，建立了胰腺上皮内瘤变和浸润性胰腺癌的转基因小鼠模型。我们将在这个模型中研究Hh信号的作用，包括在侵袭性癌症的多阶段进展过程中抑制通路的作用。作为临床试验的前奏，预测Hh拮抗剂反应性的生物标志物将通过将体外治疗反应与Hh通路基因的表达以及在50个胰腺癌细胞系中使用寡核苷酸微阵列确定的全局表达谱相关联来确定。基于Hh抑制剂在临床前研究中的有效性和对反应的预测性生物标志物的鉴定，将在不可切除的胰腺癌患者中开始使用口服生物可利用的合成Hh抑制剂进行II期临床试验。

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.