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

基本信息

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
项目类别：
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neoplasm public health relevance response stem therapy development tumor tumor microenvironment tumor progression unpublished works

项目摘要

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（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就已经转移，并且这些转移性肿瘤对细胞毒性疗法具有抵抗力。胰腺癌的治疗耐药性很大一部分来自于独特的肿瘤微环境的支持。这种肿瘤微环境包括大量浸润性骨髓细胞，包括肿瘤相关巨噬细胞，它们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，即使在耐药肿瘤中，重编程免疫微环境也将改善对细胞毒性治疗的反应。解决这个问题的一种独特方法是针对集落刺激因子 1 受体 (CSF1R)。先前的研究表明，集落刺激因子-1（一种巨噬细胞募集、存活和激活的关键细胞因子）的遗传缺失可以减缓乳腺肿瘤和神经内分泌胰腺肿瘤的进展。我们自己的工作表明，抑制 CSF1R 可以极大地改善胰腺肿瘤模型对化疗的反应并减少转移扩散。我们现在扩展了这些观察结果，并证明 CSF1R 抑制 1) 快速重新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 淋巴细胞恢复抗肿瘤细胞毒性反应。通过这样做，CSF1R 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，阻断 CSF1R 信号传导会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，为了为这些试验提供信息并检验我们的总体假设，以下具体目标至关重要。目标 1：确定巨噬细胞调节转移复发的机制。目标 2：确定 CSF1R 阻断在粒细胞重编程中的功能作用。目标 3：确定针对 CSF1R 的最佳治疗方案，以改善免疫治疗。这些目标构成了我们拟议研究的基础，该研究将结合使用临床可转化药物和遗传小鼠模型来：1）从根本上了解骨髓细胞调节化疗反应的生物学基础。 2) 识别和验证利用这些生物过程实现治疗效果的靶点。因此，该应用将开发 CSF1R 的靶向抑制作为一种新型免疫治疗剂，以改善胰腺癌患者的预后。