Targeted inhibition in stromal TGFβ activity in pancreatic cancer

胰腺癌基质 TGFβ 活性的靶向抑制

• 批准号: 10449100
• 负责人: Rolf A Brekken
• 金额: $ 35.27万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/10449100
• 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

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) 是一个有吸引力的癌症治疗靶点。 阻断 TGFβ 在胰腺癌 (PDA) 中的临床研究尚未取得成功。 部分原因是 TGFβ 信号传导抑制胰腺癌细胞的生长—— 相反，基质细胞中的 TGFβ 信号传导促进肿瘤进展。 通过诱导纤维化和免疫抑制，我们还有PDA的特征。 鉴定出 TGFβ 刺激的成纤维细胞产生限制先天免疫细胞活性的细胞因子。 例如，PDA 相关成纤维细胞产生的 IL-6 会降低 NK 细胞活性，从而促进 使用物种特异性工具，我们证明了基质的选择性抑制。 TGFβ 信号传导可减少携带 PDA 异种移植物的小鼠的 PDA 转移，并促进 这些观察结果表明上皮肿瘤细胞表型和改变的免疫微环境。 强烈表明 PDA 中基质细胞和肿瘤细胞之间存在 TGFβ 驱动的旁分泌网络 高达 60% 的人类 PDA 具有肿瘤细胞特异性缺陷。 通过 TGFβ 受体 2 (TGFβR2) 或下游信号的缺失实现经典 TGFβ 信号传导 在这里，我们提出选择性抑制基质细胞中的 TGFβ 信号传导。 携带 TGFβ 信号传导上皮突变的 PDA 将显着且安全地增强 化疗和/或免疫治疗的功效 描述所涉及的机制并进行测试。 对于这一新颖的策略，我们提出以下目标： 1、识别癌症相关的 TGFβ 信号传导 驱动PDA进展的成纤维细胞2，确定基质TGFβ抑制对PDA进展的影响； 如果得到证实，化疗和检查点阻断在 TGFβ 突变 PDA 模型中的疗效。 纠正这一点将为对 PDA 患者进行分层提供依据，以便那些患有肿瘤细胞的患者 TGFβ 信号传导的突变可能是抑制基质 TGFβ 信号传导的候选者 与标准疗法或免疫疗法相结合。