Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer

新型 Hedgehog 受体作为胰腺癌的治疗靶点

• 批准号: 8449102
• 负责人: Benjamin Allen
• 金额: $ 12.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/8449102
• 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 microenvironment; tumor xenograft

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.

描述（由申请人提供）：Hedgehog (Hh) 信号通路对于胚胎发生过程中的正确模式化和器官发育至关重要。异常的 Hh 信号活性会导致多种发育性疾病，并在多种癌症的发病机制中发挥关键作用，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，Hh 信号传导存在于多种其他癌症中，包括胰腺癌，其中肿瘤细胞衍生的 Hh 配体以旁分泌方式发出信号，以介导与周围微环境的重要相互作用。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，据信是造成这种肿瘤化疗耐药的原因。然而，对于驱动致癌 Hh 信号传导的细胞外信号传导成分知之甚少。我们建议通过系统分析 Hh 信号传导所需的三种新型细胞表面分子：Gas1、Cdo 和 Boc，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 代表新型 Hh 共受体，它们对于胚胎发生过程中多个组织中 Hh 通路的激活至关重要。 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，一个中心问题是：这些新受体在癌症 Hh 信号传导的病理激活中发挥什么作用？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 信号传导和胰腺癌方面的专业知识，以测试 Gas1、Cdo 和 Boc 是 Hh 配体驱动的胰腺癌的重要调节因子这一假设。该提案的目标是：1) 确定正常和患病胰腺中 Gas1、Cdo 和 Boc 的表达，2) 探究它们在胰腺癌中的功能，3) 生成新工具，通过靶向这些新型细胞表面受体来调节 Hh 通路。目标 1 将确定成人胰腺和胰腺癌中 Gas1、Cdo 和 Boc 的表达，并从功能上评估它们作为胰腺癌基质调节因子的功能。目标 2 将开发胰腺癌 Hh 受体的新型抑制剂并进行功能验证。拟议工作的预期成果包括：1) 详细分析成人胰腺和胰腺癌中 Gas1、Cdo 和 Boc 的表达，2) 全面评估 Gas1、Cdo 和 Boc 在胰腺癌中作为 Hh 信号传导基质调节因子的功能，以及 3) 生成一套新的治疗工具来选择性调节胰腺癌中的 Hh 通路活性。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针对这些新型 Hh 受体的化合物作为治疗目前缺乏有效治疗的胰腺癌以及其他 Hh 配体驱动的癌症的替代方法产生显着的积极影响。