Hedgehog Inhibitors in Pancreas Cancer

描述(申请人提供)：胰腺癌是一种一致致命的疾病，迫切需要有效的、基于机制的治疗来提高生存率，特别是在有转移性、不可手术肿瘤的患者中。Hhedgehog(HH)通路在大多数胰腺癌细胞系中被激活，HH小分子拮抗剂环丙胺能显著抑制体外生长。一项全面的胰腺癌HH抑制剂的临床前分析被提出，使用的体内模型概括了人类胰腺癌进展的复杂性。从切除的人胰腺癌中建立了低传代细胞系，并将用于在裸鼠胰腺组织中产生正交异性异种移植。环丙胺或口服生物可用合成HH抑制剂(基因泰克公司)将作为单一疗法使用28天。在尸检时，将通过客观的大体和组织病理学参数，包括腹内转移的发展和生存分析来评估治疗效果与对照组小鼠的疗效。HH拮抗剂和一种抗代谢物(吉西他滨)之间的协同作用将在一组异种移植癌中进行评估。通过胰腺癌基因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。在这个模型中，将研究HH信号的作用，包括抑制通路在向浸润性癌症的多阶段进展中的作用。作为临床试验的前奏，预测对HH拮抗剂反应的生物标记物将通过在50个胰腺癌细胞系中将体外治疗反应与HH途径基因的表达以及利用寡核苷酸微阵列确定的全球表达谱相关联来定义。根据HH抑制剂在临床前研究中的疗效和对反应的预测生物标志物的确定，将使用口服生物可用合成HH抑制剂在不能切除的胰腺癌患者中启动第二阶段临床试验。

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.