Hedgehog Inhibitors in Pancreas Cancer

描述（由申请人提供）：胰腺癌是一种致死性疾病，迫切需要有效的、基于机制的治疗方法来提高生存率，特别是在转移性、不可手术的肿瘤患者中。Hedgehog（Hh）途径激活见于大多数胰腺癌细胞系中，并且Hh小分子拮抗剂环巴胺可显著抑制体外生长。Hh抑制剂在胰腺癌的临床前综合分析提出，使用体内模型，概括了人类胰腺癌进展的复杂性。已从切除的人胰腺癌建立低传代细胞系，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.）将作为单药治疗给药28天。将在尸检时通过客观大体和组织病理学参数（包括腹腔内转移的发生）和生存分析评估相对于对照小鼠的给药疗效。将在异种移植癌症的子集中评估Hh拮抗剂和抗代谢物（吉西他滨）之间的协同作用。胰腺上皮内瘤变和侵袭性胰腺癌的转基因小鼠模型已经通过胰腺中致癌KRAS的错误表达而开发。在该模型中，将研究Hh信号传导的作用，包括在向浸润性癌症的多阶段进展期间抑制途径的作用。作为临床试验的前奏，预测对Hh拮抗剂的反应性的生物标志物将通过将体外治疗反应与Hh途径基因的表达和使用寡核苷酸微阵列在一组50个胰腺癌细胞系中确定的全局表达谱相关联来定义。基于Hh抑制剂在临床前研究中的疗效和对反应的预测性生物标志物的鉴定，将在患有不可切除的胰腺癌的患者中使用口服生物可利用的合成Hh抑制剂启动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.