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: 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
• 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

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）：Hedgehog（Hh）信号通路对于胚胎发生期间的正确模式和器官发育至关重要。异常的Hh信号传导活性导致许多发育性疾病，并且在包括基底细胞癌、横纹肌肉瘤和髓母细胞瘤在内的几种癌症的发病机制中起关键作用。最近的研究表明，Hh信号传导在多种其他癌症中，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必要相互作用。引人注目的是，胰腺癌的特征在于广泛的Hh驱动的纤维化基质，据信是该肿瘤的化学抗性的原因。然而，非常少的是已知的细胞外信号成分，驱动致癌Hh信号。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：Gas 1，Cdo和Boc来填补我们知识中的这一重大空白。艾伦实验室最近的研究表明，Gas 1，Cdo和Boc代表新的Hh共受体，在胚胎发生过程中的多种组织中的Hh途径激活是必不可少的。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：这些新的受体在癌症中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新的治疗方法来治疗胰腺癌。该提案是艾伦和Pasca di Magliano实验室之间的独特合作，结合了Hh信号传导和胰腺癌的专业知识，以验证Gas 1，Cdo和Boc是Hh配体驱动的胰腺癌的重要调节因子的假设。该提案的目的是：1）确定Gas 1、Cdo和Boc在正常和患病胰腺中的表达，2）询问它们在胰腺癌中的功能，以及3）通过靶向这些新的细胞表面受体产生调节Hh通路的新工具。目的1检测Gas 1、Cdo和Boc在成人胰腺和胰腺癌中的表达，并对其作为胰腺癌间质调节因子的功能进行评估。目的二是开发新型Hh受体抑制剂并进行功能验证。这项工作的预期成果包括：1）详细分析成人胰腺和胰腺癌中Gas 1，Cdo和Boc的表达，2）全面评估Gas 1，Cdo和Boc作为胰腺癌中Hh信号传导的基质调节剂的功能，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通路的活性。我们预计，这些结果将对确定Gas 1，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。 公共卫生相关性：不受控制的Hh信号传导与几种类型癌症的发展和维持有关;然而，对驱动致癌信号传导的细胞外信号传导组分知之甚少。该提案旨在填补这一 通过对胰腺癌中三种新型Hh共受体的系统功能分析，这是美国癌症相关死亡的第四大原因，五年生存率不到5%。上述初步研究可能导致开发靶向这些新型Hh受体的化合物，作为治疗胰腺癌和其他Hh配体驱动的癌症的替代方法，胰腺癌目前缺乏有效的治疗方法。