Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer

描述（由申请人提供）：Hedgehog （Hh）信号通路对于胚胎发生过程中正确的模式和器官发育至关重要。异常Hh信号活动导致许多发育疾病，并在几种癌症的发病机制中起关键作用，包括基底细胞癌、横纹肌肉瘤和髓母细胞瘤。最近的研究表明，包括胰腺癌在内的多种其他癌症中也存在Hh信号，其中肿瘤细胞衍生的Hh配体以旁分泌方式发出信号，介导与周围微环境的基本相互作用。引人注目的是，胰腺癌的特点是广泛的hh驱动的纤维化基质，这被认为是导致这种肿瘤耐药的原因。然而，对于驱动致癌Hh信号传导的细胞外信号成分，我们所知甚少。我们建议通过系统分析Hh信号传导所需的三种新的细胞表面分子：Gas1， Cdo和Boc来填补这一知识上的主要空白。Allen实验室最近的研究表明，Gas1、Cdo和Boc代表了胚胎发生过程中多种组织中Hh通路激活所必需的新型Hh共受体。Pasca di Magliano实验室的工作已经确定了Hh信号在胰腺癌中的重要作用。因此，一个核心问题是：这些新受体在癌症Hh信号的病理激活中起什么作用？这项研究的长期目标是开发治疗胰腺癌的新方法。该提案是Allen和Pasca di Magliano实验室之间的独特合作，结合了Hh信号和胰腺癌的专业知识，以验证Gas1， Cdo和Boc是Hh配体驱动的胰腺癌的重要调节因子的假设。本研究的目标是：1)确定Gas1， Cdo和Boc在正常和病变胰腺中的表达，2)询问它们在胰腺癌中的功能，3)通过靶向这些新的细胞表面受体来产生调节Hh通路的新工具。目的1将确定Gas1、Cdo和Boc在成人胰腺和胰腺癌中的表达，并从功能上评估它们作为胰腺癌间质调节因子的功能。目的2将开发和功能验证胰腺癌中Hh受体的新型抑制剂。这项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信号的间质调节因子的功能；3)产生一套新的治疗工具来选择性地调节胰腺癌中Hh通路的活性。我们预计这些结果将对确定Gas1、Cdo和Boc在胰腺癌中的基本作用以及开发靶向这些新型Hh受体的化合物作为治疗胰腺癌的替代方法产生重大的积极影响，目前缺乏有效的治疗方法，以及其他Hh配体驱动的癌症。

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.