Targeted inhibition in stromal TGFβ activity in pancreatic cancer

胰腺癌基质 TGFβ 活性的靶向抑制

基本信息

批准号：
10524152
负责人：
Rolf A Brekken
金额：
$ 13.03万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524152
关键词：
Address Cancer Cell Growth Carcinoma Cell Proliferation Cell physiology Cells Characteristics Chemoresistance Clinical Research Complement Factor B Data Diagnosis Epithelial Exons Fibroblasts Fibrosis Gene Expression Profile Gene Frequency Goals Growth Hematopoietic Heterogeneity Human Immune Immunosuppression Immunotherapy Interleukin-6 MADH4 gene Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Modeling Mus Mutation Natural Killer Cells Neoplasm Metastasis Pancreatic Ductal Adenocarcinoma Paracrine Communication Pathway interactions Patients Pharmacology Phenotype Production Proteins Public Health Reporting STAT3 gene Signal Pathway Signal Transduction Signaling Protein Stromal Cells Stromal Neoplasm TGFBR2 gene Testing Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transforming Growth Factors Treatment Efficacy Tumor Promotion Xenograft procedure cancer cell chemotherapy cytokine driver mutation druggable target immune checkpoint blockade loss of function mutation mouse model mutant neoplastic cell novel strategies pancreatic cancer cells pancreatic cancer model pancreatic cancer patients paracrine patient derived xenograft model patient stratification preclinical study receptor response therapeutic target tool tumor tumor progression tumor-immune system interactions

项目摘要

Transforming growth factor β (TGFβ) is an attractive therapeutic target in cancer. However, blocking TGFβ in pancreatic cancer (PDA) has not been successful in clinical studies. This is due part to the fact that TGFβ signaling suppresses pancreatic cancer cell growth in a context- dependent manner. In contrast, TGFβ signaling in stromal cells promotes to tumor progression by inducing fibrosis and immunosuppression, characteristics of PDA. Moreover, we have identified TGFβ-stimulated fibroblasts produce cytokines that limit innate immune cell activity. For example, IL-6 production by PDA associated fibroblasts reduces NK cell activity that facilitates PDA metastasis. Using species specific tools we demonstrated that selective inhibition of stromal TGFβ signaling reduces PDA metastasis in mice bearing PDA xenografts and also promotes an epithelial tumor cell phenotype and an altered immune microenvironment. These observations strongly suggest a TGFβ-driven paracrine network between stromal cells and tumor cells in PDA that promotes tumor progression. Up to 60% of human PDA have tumor cell specific deficiency in canonical TGFβ signaling via loss of TGFβ receptor 2 (TGFβR2) or the downstream signal mediator SMAD4. Here we propose that selective inhibition of TGFβ signaling in stromal cells in PDA that harbors epithelial mutations in TGFβ signaling will dramatically and safely enhance the efficacy of chemotherapy and/or immune therapy. To delineate the mechanisms involved and test this novel strategy, we propose the following aims: 1, Identify TGFβ signaling in cancer associated fibroblasts that drive PDA progression; 2, Determine the effect of stromal TGFβ inhibition on the efficacy of chemotherapy and checkpoint blockade in models of TGFβ mutant PDA. If proven correct this would provide a rationale to stratify PDA patients such that those with tumor cell mutations in TGFβ signaling would be candidates for inhibition of stromal TGFβ signaling in combination with standard therapy or immune therapy.

转化生长因子β（TGFβ）是癌症中有吸引力的治疗靶标。然而，胰腺癌（PDA）中阻断TGFβ在临床研究中尚未成功。这是应得的一部分TGFβ信号传导在环境中抑制胰腺癌细胞的生长依赖方式。相反，基质细胞中的TGFβ信号转导促进肿瘤进展通过诱导纤维化和免疫抑制，PDA的特征。而且，我们有鉴定出TGFβ刺激的成纤维细胞产生了限制先天免疫细胞活性的细胞因子。为了例如，IL-6与PDA相关的成纤维细胞产生可减少促进的NK细胞活性 PDA转移。使用规格特定的工具，我们证明了选择性抑制基质 TGFβ信号传导减少带有PDA Xenographtics的小鼠中的PDA转移，还促进了上皮肿瘤细胞表型和免疫微环境改变。这些观察强烈建议PDA中基质细胞和肿瘤细胞之间的TGFβ驱动的旁分泌网络促进肿瘤进展。多达60％的人PDA具有肿瘤细胞特异性缺陷通过TGFβ受体2（TGFβR2）或下游信号的丢失，经典TGFβ信号传导介体SMAD4。在这里，我们提出选择性抑制在基质细胞中TGFβ信号传导的选择性抑制 PDA具有TGFβ信号传导中上皮突变的PDA将显着，安全地增强化学疗法和/或免疫治疗的功效。描述涉及和测试的机制这种新型策略，我们提出以下目的：1，确定与癌症相关的癌症中的TGFβ信号传导驱动PDA进展的成纤维细胞； 2，确定基质TGFβ对 TGFβ突变体PDA模型中化学疗法和检查点阻滞的功效。如果经过证明纠正这将提供分层PDA患者的理由，使患有肿瘤细胞的患者 TGFβ信号中的突变将是抑制基质TGFβ信号传导的候选者结合标准疗法或免疫疗法。