REPROGRAMMING THE METASTATIC MICROENVIRONMENT OF PANCREATIC CANCER THROUGH CSF1R

通过 CSF1R 重新编程胰腺癌的转移微环境

• 批准号: 8694239
• 负责人: David G DeNardo
• 金额: $ 31.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694239
• 关键词: Acute; Address; Adenocarcinoma Cell; Adjuvant; Antigen Presentation; Antitumor Response; Biological; Biological Process; Biological Response Modifiers; CD8B1 gene; CSF1 gene; CXCL10 gene; CXCL11 gene; Cancer Patient; Cells; Chemoprotection; Chemosensitization; Clinical; Clinical Trials; Cytotoxic Chemotherapy; Cytotoxic T-Lymphocytes; Cytotoxic agent; Dendritic Cells; Detection; Development; Diagnosis; Disease; Frequencies; Genetic; Goals; Granulocyte Precursor Cells; Growth; Immature Granulocyte; Immature Monocyte; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Infiltration; Islet Cell Tumor; Leukocytes; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammary Neoplasms; Mammary gland; Mediating; Mediator of activation protein; Medical; Modeling; Mus; Myelogenous; Myeloid Cells; Natural Killer Cells; Neoplasm Metastasis; Neuroendocrine Tumors; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phase; Primary Neoplasm; Property; Publishing; Reagent; Receptor Inhibition; Receptor Signaling; Recovery; Regimen; Relapse; Research; Resistance; Role; Signal Pathway; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Tumor Immunity; Work; base; cancer cell; cancer stem cell; chemotherapy; clinical application; cytokine; cytotoxic; design; effective therapy; granulocyte; improved; insight; macrophage; mouse model; neutrophil; novel; outcome forecast; palliative; pancreatic neoplasm; public health relevance; response; stem; therapy development; tumor; tumor microenvironment; tumor progression; unpublished works

DESCRIPTION (provided by applicant): The prognosis for pancreatic cancer (PC) patients is dismal, with a 5-year survival rate of less than 6%. This is in part due to the propensity of PC to metastasize prior to disease detection and the resistance of these metastatic tumors to cytotoxic therapies. A significant portion of therapeutic resistance in pancreatic cancers comes from the support of a unique tumor microenvironment. This tumor microenvironment includes significant numbers of infiltrating myeloid cells including tumor-associated macrophages, which exacerbate responses to therapy by inducing immunosuppression and increasing the presence of cancer stem cells. Thus, where clinically feasible reprogramming the immune microenvironment would improve responses to cytotoxic therapy even in resistant tumors. One unique approach to this problem is to target the colony-stimulating factor 1 receptor (CSF1R). Previous studies have shown that genetic loss of colony stimulating factor-1, a critical cytokine for the recruitment, survival, and activation of macrophages, can decease the progression of mammary and neuroendocrine pancreatic tumors. Our own work has shown that inhibiting CSF1R can vastly improve responses to chemotherapy and decrease metastatic spread in pancreatic tumor models. We have now extended these observations and demonstrated that CSF1R inhibition 1) rapidly reprograms tumor-infiltrating macrophage responses, 2) decreases the frequency of tumor initiating cells, and 3) leads to recovery of anti-tumor cytotoxic responses by neutrophils and T lymphocytes. In so doing, CSF1R inhibition reprograms the tumor microenvironment to increase responses to chemotherapy and decrease metastatic spread. Thus, our hypothesis is that blockade of CSF1R signaling reprograms the tumor microenvironment to improve responses to chemo- and immunotherapy. The long-term goals of the proposed studies are to initiate new clinical trials testing this approach in metastatic PC. However, in order to inform these trials and test our overall hypothesis the following specific aims are critical. Aim 1: Determine the mechanisms by which macrophages regulate metastatic relapse. Aim 2: Determine the functional role of CSF1R blockade in granulocyte reprogramming. Aim 3: Determine the optimum therapeutic regimen for targeting CSF1R to improve immunotherapy. These Aims form the basis of our proposed studies, which will use a combination of clinically translatable agents and genetic mouse models to: 1) fundamentally understand the biological underpinnings by which myeloid cells regulate chemotherapeutic response. And 2) to identify and validate targets to exploit these biological processes for therapeutic benefit. Thus, this application will develop targeted inhibition of CSF1R as a novel immunotherapeutic agent to improve outcomes for pancreatic cancer patients.

描述（由申请人提供）：胰腺癌（PC）患者的预后很差，5年生存率低于6%。这部分是由于PC的倾向， 在疾病检测之前转移和这些转移性肿瘤对细胞毒性疗法的抗性。胰腺癌的治疗耐药性很大一部分来自独特的肿瘤微环境的支持。这种肿瘤微环境包括大量的浸润性骨髓细胞，包括肿瘤相关巨噬细胞，其通过诱导免疫抑制和增加癌症干细胞的存在来加剧对治疗的反应。因此，在临床上可行的情况下，重编程免疫微环境将改善对细胞毒性疗法的应答，即使在抗性肿瘤中也是如此。解决这个问题的一个独特方法是靶向集落刺激因子1受体（CSF 1 R）。以前的研究表明，集落刺激因子-1（巨噬细胞募集、存活和活化的关键细胞因子）的遗传缺失可以减缓乳腺和神经内分泌胰腺肿瘤的进展。我们自己的工作表明，抑制CSF 1 R可以大大改善对化疗的反应，并减少胰腺肿瘤模型的转移扩散。我们现在已经扩展了这些观察结果，并证明CSF 1 R抑制1）快速重编程肿瘤浸润巨噬细胞反应，2）降低肿瘤起始细胞的频率，3）导致中性粒细胞和T淋巴细胞的抗肿瘤细胞毒性反应恢复。在这样做的过程中，CSF 1 R抑制重新编程肿瘤微环境，以增加对化疗的反应并减少转移扩散。因此，我们的假设是，CSF 1 R信号传导的阻断重新编程肿瘤微环境，以改善对化疗和免疫治疗的反应。拟议研究的长期目标是启动新的临床试验，在转移性PC中测试这种方法。然而，为了告知这些试验并测试我们的总体假设，以下特定目标至关重要。目的1：确定巨噬细胞调节转移复发的机制。目的2：确定CSF 1 R阻断在粒细胞重编程中的功能作用。目的3：确定以CSF 1 R为靶点的最佳治疗方案，以提高免疫治疗效果。这些目标构成了我们提出的研究的基础，这些研究将使用临床可翻译的药物和遗传小鼠模型的组合来：1）从根本上理解骨髓细胞调节化疗反应的生物学基础。和2）鉴定和验证靶点以利用这些生物过程获得治疗益处。因此，本申请将开发CSF 1 R的靶向抑制作为一种新型免疫抑制剂，以改善胰腺癌患者的预后。