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: 9021619
• 负责人: David G DeNardo
• 金额: $ 31.64万
• 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/9021619
• 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; Health; 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; Myelogenous; Myeloid Cells; Natural Killer Cells; Neoplasm Metastasis; Neuroendocrine Tumors; 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; improved outcome; insight; macrophage; mouse model; neutrophil; novel; outcome forecast; palliative; pancreatic neoplasm; response; stem; targeted treatment; therapy development; therapy resistant; tumor; tumor microenvironment; tumor progression; unpublished works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年生存率不到6%。这部分是由于个人电脑倾向于