COMBINED TUMOR AND STROMAL TARGETING TO IMPROVE PANCREATIC CANCER RESPONSE TO IMMUNOTHERAPY

肿瘤和间质联合靶向改善胰腺癌对免疫治疗的反应

• 批准号: 9077612
• 负责人: David G DeNardo
• 金额: $ 34.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-07 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077612
• 关键词: 3-Dimensional; Adenocarcinoma Cell; Antigens; Cancer Patient; Cell physiology; Cessation of life; Clinical; Clinical Trials; Cytotoxic agent; Data; Development; Disease Progression; Effectiveness; Engineering; Fibrosis; Focal Adhesion Kinase 1; Functional disorder; Genetic; Genetic Engineering; Human; Immune; Immunobiology; Immunologic Surveillance; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammation; Inflammatory; KRAS2 gene; Laboratories; Malignant neoplasm of pancreas; Mediator of activation protein; Medical; Modeling; Molecular; Mus; Mutate; Myelogenous; Myeloid Cells; Oncogenes; Oncogenic; PTK2 gene; PTK2B gene; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Resistance; Signal Pathway; Signal Transduction; Signaling Molecule; Stromal Cells; Stromal Neoplasm; T cell response; T-Lymphocyte; Testing; Therapeutic; Tumor Immunity; Tumor Pathology; base; cancer cell; chemotherapy; density; design; improved; inhibitor/antagonist; kinase inhibitor; macrophage; melanoma; mouse model; mutant; neoplastic cell; novel; outcome forecast; pancreatic neoplasm; pre-clinical; prevent; programs; public health relevance; response; tumor; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): The prognosis for pancreatic cancer (PaC) patients is dismal. The application of immunotherapy holds the promise to revolutionize PaC patient outcomes. Unfortunately, attempts at immunotherapy in PaC, to date, have not achieved significant clinical benefits as single agents. This is likely due to the presence of a uniquely suppressive tumor microenvironment (TME) that is dominant in most pancreatic ductal adenocarcinomas (PDAC). Two major drivers of this tumor protective microenvironment include a dense fibrotic tumor stroma and robust infiltration by tumor-supportive myeloid cells. High stromal density provides a barrier to T cell infiltration and function. These data suggest that we could improve PaC patient outcomes, if we could identify therapeutics that reprogram the protective TME to facilitate immunotherapy. One such approach is to target the oncogenic pathways that induce the fibrotic and suppressive PDAC TME. Recently, we have identified focal adhesion kinase (FAK)-1, which is hyperactivated in the presence of mutated Kras, as a major driver of the fibrotic and inflammatory (fibro-inflammatory) TME of PDAC tumors. We have discovered that in human PDAC, elevated FAK activity correlates with higher fibrosis levels, excessive myeloid cell infiltration, and poor T cell responses. These data suggest that FAK is a key mediator of the fibro-inflammatory microenvironment that blocks immunotherapeutic efficacy. We have found that FAK inhibition dramatically reduced fibrosis and inflammatory myeloid cell infiltration, and improved T cell function in PaC mouse models. Our hypothesis is that: Reciprocal crosstalk between Kras-mutant pancreatic tumors and stromal cells regulates inflammatory fibrosis and prevents responsiveness to immunotherapy. To test this hypothesis, we will: 1) Determine the mechanisms by which Kras-driven FAK activity regulates fibrosis and local immunosuppression. 2) Determine the impact of stromal FAK signaling on fibrosis and tumor progression. 3) Determine the mechanisms by which FAK blockade improves immunotherapy. Significance: Our preliminary data strongly support the use of FAK inhibitors in combination with chemotherapy and/or checkpoint antagonists in PDAC patients. However, understanding the mechanisms by which FAK signaling in PDAC tumor and stromal cells drive tumor fibrosis and immunosuppression is critical to designing effective clinica trials. Additionally, these studies will contribute to our understanding of how tumor cells and stromal cells crosstalk to generate resistance to immunotherapy. This is a significant gap in our understanding of the immunobiology of PaC, which has thwarted the effectiveness of therapy to date.

 描述（由申请人提供）：胰腺癌（PaC）患者的预后很差。免疫疗法的应用有望彻底改变 PaC 患者的治疗结果。不幸的是，迄今为止，针对 PaC 的免疫治疗尝试作为单一药物尚未取得显着的临床益处。这可能是由于存在独特的抑制性肿瘤微环境（TME），这种微环境在大多数胰腺导管腺癌（PDAC）中占主导地位。这种肿瘤保护性微环境的两个主要驱动因素包括致密的纤维化肿瘤基质和肿瘤支持性骨髓细胞的强大浸润。高基质密度为 T 细胞浸润和功能提供了屏障。这些数据表明，如果我们能够找到重新编程保护性 TME 以促进免疫治疗的治疗方法，我们就可以改善 PaC 患者的治疗结果。其中一种方法是针对诱导纤维化和抑制性 PDAC TME 的致癌途径。 最近，我们发现粘着斑激酶 (FAK)-1 在 Kras 突变的情况下过度激活，是 PDAC 肿瘤纤维化和炎症 (纤维炎症) TME 的主要驱动因素。我们发现，在人类 PDAC 中，FAK 活性升高与较高的纤维化水平、过度的骨髓细胞浸润和 T 细胞反应较差相关。这些数据表明 FAK 是阻碍免疫治疗功效的纤维炎症微环境的关键介质。我们发现，FAK 抑制可显着减少 PaC 小鼠模型中的纤维化和炎性骨髓细胞浸润，并改善 T 细胞功能。我们的假设是：Kras 突变胰腺肿瘤和基质细胞之间的相互串扰调节炎症纤维化并防止对免疫治疗的反应。为了检验这一假设，我们将：1）确定 Kras 驱动的 FAK 活性调节纤维化和局部免疫抑制的机制。 2) 确定基质FAK信号传导对纤维化和肿瘤进展的影响。 3) 确定 FAK 阻断改善免疫治疗的机制。意义：我们的初步数据强烈支持在 PDAC 患者中将 FAK 抑制剂与化疗和/或检查点拮抗剂联合使用。然而，了解 PDAC 肿瘤和基质细胞中 FAK 信号传导驱动肿瘤纤维化和免疫抑制的机制对于设计有效的临床试验至关重要。此外，这些研究将有助于我们了解肿瘤细胞和基质细胞如何相互作用以产生对免疫治疗的耐药性。这是我们对 PaC 免疫生物学理解的重大差距，迄今为止，这阻碍了治疗的有效性。