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，特别是胰腺导管腺癌 (PDAC)，是美国癌症死亡的第四大原因，其 5 年生存率约为 5%。造成生存率低下的一个关键因素是 PDAC 的广泛结缔组织形成（丰富的纤维化基质），这使得手术切除肿瘤变得困难，并限制治疗药物进入肿瘤细胞。癌症相关成纤维细胞 (CAF) 是产生细胞外基质蛋白的肌成纤维细胞样细胞，负责 PDAC 中的结缔组织形成。胰腺星状细胞 (PSC) 和成纤维细胞 (PF) 是 CAF 的关键祖细胞。阻断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 的一个重要的、尚未得到充分研究的方面，并且可能是治疗胰腺癌的新靶点。 GPCR 是最大的细胞表面信号传导受体家族（占人类基因组的 3%），调节许多生理过程。作为质膜蛋白，GPCR 可从细胞外空间进入； GPCR 在细胞类型和组织上选择性表达，并在配体相互作用因子中表现出特异性，这有助于解释为什么 GPCR 是目前约 30% 的治疗药物的靶标，尽管不是在肿瘤学中。该 R21 旨在通过识别、量化和验证人胰腺 CAF 的 GPCR 表达，以及评估 CAF 选择性表达的 GPCR 的治疗潜力（与 PSC 和 PF 相比）来实现变革。该项目使用患者来源的胰腺 CAF 作为模型，并将使用多种基因组策略：GPCRomic 方法量化所有非化学感应 GPCR 的基因表达，使用 RNA 干扰敲低 CAF 表达的 GPCR 并识别介导关键功能反应的 GPCR通过使用正常胰腺成纤维细胞或胰腺星状细胞进行功能获得研究，并通过增强 CAF 的表达来重现 CAF 的纤维化表型PSC 和 PF 中的 GPCR。目标是利用基因组方法通过 GPCR 阻断 CAF 表达和促纤维化活性的能力，将其识别为治疗胰腺癌的潜在靶点。我们将采用的策略 - GPCR 基因家族成员的 GPCR 组学以及该家族成员在人类疾病中（在本例中为胰腺癌相关成纤维细胞）的功能获得和功能丧失研究 - 是一种新颖的策略这应该很容易适用于其他癌症和其他疾病环境中的 CAF。此外，该提案的另一个新颖且具有临床意义的方面是它开始努力测试以下想法：CAF（特别是胰腺 CAF）上的 GPCR 可能是迫切需要新疗法的疾病的药物靶点。