GPCRs: novel targets in cancer-associated fibroblasts

GPCR：癌症相关成纤维细胞的新靶点

• 批准号: 8773037
• 负责人: PAUL A INSEL
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773037
• 关键词: Adenocarcinoma Cell; Biological; Biological Assay; Cancer Etiology; Cause of Death; Cell Proliferation; Cell Surface Proteins; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Collagen; Complement; Cyclic AMP; Desmin; Disease; Enzymes; Extracellular Matrix Proteins; Extracellular Space; Family; Family member; Fibroblasts; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; G-substrate; GTP Binding; GTP-Binding Proteins; Gene Expression; Gene Family; Genomics; Goals; Growth; Growth Factor; Human; Human Genome; Ligands; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane Proteins; Metabolism; Modeling; Molecular Weight; Mutation; Myofibroblast; Neoplasm Metastasis; Neurotransmitters; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological Processes; Production; Proteins; RNA Interference; Receptor Cell; Receptor Signaling; Relative (related person); Role; Second Messenger Systems; Signal Transduction; Smooth Muscle Actin Staining Method; Specificity; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Tumor Tissue; base; cell type; cytokine; functional genomics; gain of function; human disease; improved; interstitial; loss of function; member; migration; neoplastic cell; new therapeutic target; novel; oncology; outcome forecast; pressure; progenitor; public health relevance; receptor expression; response; second messenger; selective expression; stellate cell; therapeutic target; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC), is the fourth leading cause of cancer death in the U.S. and has a 5-year survival of ~ 5%. A key contributor to this poor survival is the extensive desmoplasia (abundant fibrotic stroma) of PDAC, which can make it difficult to surgically remove the tumor and can limit access of therapeutic drugs to the tumor cells. Cancer-associated fibroblasts (CAFs), myofibroblast-like cells that produce extracellular matrix proteins, are responsible for the desmoplasia in PDAC. Pancreatic stellate cells (PSCs) and fibroblasts (PFs) are key progenitors of CAFs. Blocking the expression and activity of CAFs may be a means to improve the therapy and prognosis of PDAC. This proposal posits that G-protein-coupled receptors (GPCRs) are an important, understudied aspect of pancreatic CAFs and may be novel targets for the treatment of pancreatic cancer. GPCRs are the largest family of cell surface signaling receptors (3% of the human genome) and regulate many physiological processes. As plasma membrane proteins, GPCRs are accessible from the extracellular space; GPCRs are selectively expressed on cell types and tissues and show specificity in ligand interaction-factors that help explain why GPCRs are the targets for ~30% of current therapeutic agents albeit not in oncology. This R21 seeks to be transformative by identifying, quantifying and validating the expression of GPCRs by human pancreatic CAFs, and by assessing the therapeutic potential of GPCRs selectively expressed by CAFs (compared to PSCs and PFs). The project uses patient-derived pancreatic CAFs as a model and will use several genomic strategies: a GPCRomic approach to quantify gene expression of all non-chemosensory GPCRs, use of RNA interference knockdown GPCRs expressed by CAFs and identify the GPCRs that mediate key functional responses and gain-of-function studies by using normal pancreatic fibroblasts or pancreatic stellate cells and seeking to recapitulate the fibrotic phenotype of CAFs by enhancing expression of GPCRs in PSCs and PFs. The goal is to use genomic approaches to identify GPCRs as potential targets for the treatment of pancreatic cancer through their ability to block expression and pro-fibrotic activity of CAFs. The strategy that we will employ- GPCRomics of members of the GPCR gene family and gain of function and loss of function studies with members of this family in a human disease (in this case, in pancreatic cancer-associated fibroblasts)-is a novel one that should be readily applicable to CAFs in other cancers and to other disease settings. In addition, a further novel and clinically important aspect of this proposl is its initiation of efforts to test the idea that GPCRs on CAFs (in particular pancreatic CAFs) may be druggable targets for a disease that is in desperate need of new therapies.

描述（由申请人提供）：胰腺癌，尤其是胰腺导管腺癌（PDAC），是美国癌症死亡的第四个主要原因，5年生存率约为5％。 PDAC的广泛的脱木质（丰富的纤维化基质）是，这可能使得难以通过手术去除肿瘤，并且可以限制治疗药物对肿瘤细胞的访问。与癌症相关的成纤维细胞（CAF），产生细胞外基质蛋白的肌纤维细胞样细胞是PDAC中的脱木质的。胰腺星状细胞（PSC）和成纤维细胞（PFS）是CAF的关键祖细胞。阻止CAF的表达和活性可能是改善PDAC治疗和预后的一种手段。该提案认为，G蛋白偶联受体（GPCR）是胰腺CAF的重要，研究的方面，可能是治疗胰腺癌的新靶标。 GPCR是最大的细胞表面信号受体家族（占人类基因组的3％），并调节许多生理过程。作为质膜蛋白，可以从细胞外空间进入GPCR。 GPCR在细胞类型和组织上有选择地表达，并在配体相互作用因子中显示出特异性，这有助于解释为什么GPCR是〜30％的当前治疗剂的靶标，尽管不在肿瘤学中。该R21试图通过识别，量化和验证人类胰腺CAF的GPCR表达，并通过评估CAF选择性表达的GPCR的治疗潜力（与PSC和PFS相比）。该项目使用患者来源的胰CAF作为模型，将使用多种基因组策略：一种GPCROMIC方法来量化所有非化学感官GPCR的基因表达，使用RNA干扰敲低的GPCR，由CAF表达并通过介导的GPCR来介导关键功能响应和使用正常的PANCROTIC PRACREAT PANCREAT PANCREAT PANCREAT PANCREAT PARTICENTIC PARTICENTIC PARTIC，细胞并试图通过增强PSC和PFS中GPCR的表达来概括CAF的纤维化表型。目的是使用基因组方法来鉴定GPCR通过阻止CAF的表达和促纤维化活性来治疗胰腺癌的潜在靶标。我们将采用GPCR基因家族成员的GPCROMICS，以及在人类疾病中与该家族成员的功能和功能研究的损失（在这种情况下，在胰腺癌相关的成纤维细胞中） - 这是一种新颖的新颖，是一种新颖的，应该很容易适用于其他癌症和其他疾病环境中的CAF。此外，该建议的另一个新颖且临床上重要的方面是它开始努力测试CAFS上的GPCR（尤其是胰腺CAF）的想法，这可能是迫切需要新疗法的疾病的可药物目标。