Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer

新型 Hedgehog 受体作为胰腺癌的治疗靶点

基本信息

批准号：
8285346
负责人：
Benjamin Allen
金额：
$ 23.67万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8285346
关键词：
Adult Antibodies Basal cell carcinoma Blocking Antibodies Cancer Etiology Cell Culture Techniques Cell Surface Receptors Cell surface Cessation of life Clinical Trials Collaborations Development Disease Drug resistance Electroporation Embryonic Development Erinaceidae Fibroblasts Future Generations Generations Genetically Engineered Mouse Goals Growth Human In Situ Hybridization Knowledge Laboratories Lead Ligands Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mus Oncogenic Organ Outcome Pancreas Pathogenesis Pathologic Pathway interactions Patients Pattern Peptides Pilot Projects Play Proteins Reporter Research Resistance Rhabdomyosarcoma Role Signal Transduction Survival Rate Testing Therapeutic Therapeutic Uses Tissues Transplantation United States Validation Variant Work Xenograft procedure cancer type effective therapy extracellular human SMO protein in vivo inhibitor/antagonist medulloblastoma mouse model neoplastic cell novel novel strategies novel therapeutic intervention paracrine receptor receptor expression small molecule smoothened signaling pathway therapeutic target tool tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): The Hedgehog (Hh) signaling pathway is vital for proper patterning and organ development during embryogenesis. Aberrant Hh signaling activity causes numerous developmental diseases and plays a pivotal role in the pathogenesis of several cancers, including basal cell carcinoma, rhabdomyosarcoma, and medulloblastoma. More recent studies implicate Hh signaling in multiple additional cancers, including pancreatic cancer, where tumor cell derived Hh ligands signal in a paracrine manner to mediate essential interactions with the surrounding microenvironment. Strikingly, pancreatic cancer is characterized by an extensive Hh-driven fibrotic stroma, believed to be responsible for the chemo-resistance of this tumor. However, remarkably little is known about the extracellular signaling components that drive oncogenic Hh signaling. We propose to fill this major gap in our knowledge through a systematic analysis of three novel, cell surface molecules that are required for Hh signaling: Gas1, Cdo and Boc. Recent studies from the Allen lab indicate that Gas1, Cdo and Boc represent novel Hh co-receptors that are essential for Hh pathway activation in multiple tissues during embryogenesis. Work from the Pasca di Magliano lab has identified an important role for Hh signaling in pancreatic cancer. Thus, a central question is: what roles do these novel receptors play in the pathologic activation of Hh signaling in cancer? The long-term goal of this research is to develop new therapeutic approaches to the treatment of pancreatic cancer. This proposal is a unique collaboration between the Allen and Pasca di Magliano labs that combines expertise in Hh signaling and pancreatic cancer to test the hypothesis that that Gas1, Cdo and Boc are essential regulators of Hh ligand-driven pancreatic cancer. The objectives of this proposal are to: 1) determine the expression of Gas1, Cdo and Boc in normal and diseased pancreas, 2) interrogate their function in pancreatic cancer and 3) generate new tools to modulate the Hh pathway by targeting these novel cell surface receptors. Aim 1 will determine the expression of Gas1, Cdo and Boc in adult pancreas and pancreatic cancer and functionally assess their function as stromal regulators of pancreatic cancer. Aim 2 will develop and functionally validate novel inhibitors of Hh receptors in pancreatic cancer. The expected outcomes of the proposed work include: 1) a detailed analysis of Gas1, Cdo and Boc expression in the adult pancreas and pancreatic cancer, 2) a comprehensive assessment of Gas1, Cdo and Boc function as stromal regulators of Hh signaling in pancreatic cancer, and 3) the generation of a new set of therapeutic tools to selectively modulate Hh pathway activity in pancreatic cancer. We expect that these results will have a significant positive impact on determining the fundamental roles of Gas1, Cdo and Boc in pancreatic cancer and on the development of compounds targeting these novel Hh receptors as an alternative approach to treat pancreatic cancer, which currently lacks effective treatments, as well as other Hh ligand-driven cancers. PUBLIC HEALTH RELEVANCE: Uncontrolled Hh signaling is implicated in the development and maintenance of several types of cancer; however, remarkably little is known about the extracellular signaling components that drive oncogenic signaling. This proposal seeks to fill this gap through a systematic functional analysis of three novel Hh co-receptors in pancreatic cancer, which is the fourth leading cause of cancer-related death in the United States, with a five-year survival rate of less than five percent. The pilot studies proposed above may lead to the development of compounds that target these novel Hh receptors as an alternative approach to treat pancreatic cancer, which currently lacks effective treatments, and other Hh ligand-driven cancers.

描述（由申请人提供）：刺猬（HH）信号通路对于胚胎发生过程中适当的图案和器官发育至关重要。异常的HH信号传导活性引起许多发育疾病，并且在几种癌症的发病机理中起关键作用，包括基底细胞癌，横纹肌肉瘤和髓母细胞瘤。最近的研究暗示了包括胰腺癌在内的多种其他癌症中的HH信号传导，其中肿瘤细胞以旁分泌的方式衍生出HH配体信号，以介导与周围微环境的基本相互作用。令人惊讶的是，胰腺癌的特征是广泛的HH驱动基质，据信是该肿瘤的化学耐药性。但是，对于驱动致癌HH信号的细胞外信号传导成分知之甚少。我们建议通过对HH信号传导所需的三个新型细胞表面分子进行系统分析来填补这一主要空白：GAS1，CDO和BOC。来自Allen Lab的最新研究表明，GAS1，CDO和BOC代表了新型HH共受体，这对于胚胎发生过程中多个组织中的HH途径激活至关重要。 Pasca di Magliano实验室的工作确定了HH信号在胰腺癌中的重要作用。因此，一个核心问题是：这些新型受体在癌症中HH信号传导的病理激活中起什么作用？这项研究的长期目标是开发用于治疗胰腺癌的新治疗方法。该提议是艾伦（Allen）和帕斯卡·迪·玛格丽亚诺（Pasca Di Magliano）实验室之间的独特合作，结合了HH信号传导和胰腺癌的专业知识，以检验以下假设：GAS1，CDO和BOC是HH配体驱动的胰腺癌的基本调节剂。该提案的目标是：1）确定正常和患病胰腺中气体，CDO和BOC的表达，2）询问其在胰腺癌中的功能，3）生成新工具来通过靶向这些新型细胞表面受体来调节HH途径。 AIM 1将确定成人胰腺和胰腺癌中GAS1，CDO和BOC的表达，并在功能上评估其作为胰腺癌基质调节剂的功能。 AIM 2将开发并在功能上验证胰腺癌中HH受体的新型抑制剂。 The expected outcomes of the proposed work include: 1) a detailed analysis of Gas1, Cdo and Boc expression in the adult pancreas and pancreatic cancer, 2) a comprehensive assessment of Gas1, Cdo and Boc function as stromal regulators of Hh signaling in pancreatic cancer, and 3) the generation of a new set of therapeutic tools to selectively modulate Hh pathway activity in pancreatic cancer.我们预计，这些结果将对确定胰腺癌中GAS1，CDO和BOC的基本作用以及针对这些新型HH受体作为治疗胰腺癌的替代方法的化合物的发展产生重大的积极影响，该化合物目前缺乏有效的治疗方法，以及其他HH配体驱动型癌症。公共卫生相关性：不受控制的HH信号与几种类型的癌症的发展和维持有关；但是，对于驱动致癌信号传导的细胞外信号传导组件知之甚少。该建议旨在填补这个通过对胰腺癌中三个新型HH共受体的系统功能分析的差距，这是美国与癌症相关死亡的第四个主要原因，五年生存率少于5％。上面提出的试点研究可能导致靶向这些新型HH受体的化合物，作为治疗胰腺癌的替代方法，目前缺乏有效的治疗方法，以及其他HH配体驱动的癌症。