Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer

描述(由申请人提供)：Hedgehog(HH)信号通路在胚胎发育过程中对正确的模式和器官发育至关重要。HH信号活性异常可导致多种发育性疾病，并在包括基底细胞癌、横纹肌肉瘤和髓母细胞瘤在内的多种癌症的发病机制中发挥关键作用。最近的研究表明，HH信号与多种其他癌症有关，包括胰腺癌，肿瘤细胞以旁分泌方式获得HH配体信号，以介导与周围微环境的必要相互作用。值得注意的是，胰腺癌的特点是广泛的HH驱动的纤维间质，被认为是这种肿瘤耐药的原因。然而，人们对驱动致癌HH信号的细胞外信号成分知之甚少。我们建议通过对HH信号所需的三个新的细胞表面分子：Gas1、CDO和Boc的系统分析来填补我们知识中的这一主要空白。Allen实验室最近的研究表明，Gas1、CDO和Boc代表着新的HH辅助受体，在胚胎发育过程中多个组织中HH途径的激活是必不可少的。帕斯卡·迪·马格里亚诺实验室的研究已经确定了HH信号在胰腺癌中的重要作用。因此，一个中心问题是：这些新的受体在癌症中HH信号的病理激活中扮演什么角色？这项研究的长期目标是开发治疗胰腺癌的新方法。这项建议是Allen和Pasca di Magliano实验室之间的独特合作，将HH信号和胰腺癌方面的专业知识结合在一起，以测试Gas1、CDO和Boc是HH配体驱动的胰腺癌的必要调节因子的假设。本研究的目的是：1)确定Gas1、CDO和Boc在正常胰腺和病变胰腺中的表达；2)探讨它们在胰腺癌中的作用；3)通过靶向这些新的细胞表面受体，开发新的工具来调控HH通路。目的1检测Gas1、CDO和Boc在成人胰腺和胰腺癌中的表达，从功能上评价它们作为胰腺癌基质调节因子的作用。AIM 2将开发并从功能上验证胰腺癌HH受体的新型抑制剂。这项拟议工作的预期结果包括：1)详细分析Gas1、CDO和Boc在成人胰腺和胰腺癌中的表达，2)全面评估Gas1、CDO和Boc在胰腺癌中作为HH信号间质调节因子的功能，以及3)产生一套新的治疗工具来选择性地调节胰腺癌中HH途径的活性。我们预计，这些结果将对确定Gas1、CDO和Boc在胰腺癌中的基础作用以及针对这些新型HH受体的化合物的开发产生重要的积极影响，作为治疗胰腺癌和其他HH配体驱动的癌症的替代方法。 公共卫生相关性：不受控制的HH信号与几种类型癌症的发生和维持有关；然而，对驱动致癌信号的细胞外信号成分知之甚少。这项提议旨在填补这一点 GAP通过对胰腺癌中三种新的HH辅助受体进行系统的功能分析，胰腺癌是美国癌症相关死亡的第四大原因，五年存活率不到5%。上述建议的试点研究可能导致针对这些新型HH受体的化合物的开发，作为治疗胰腺癌和其他HH配体驱动的癌症的替代方法。

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.