(PQB-3) Driver gene-induced inflammation in pancreatic cancer development

(PQB-3) 驱动基因诱导的胰腺癌发展中的炎症

• 批准号: 9042316
• 负责人: ELIZABETH M. JAFFEE
• 金额: $ 76.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042316
• 关键词: Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Automobile Driving; B-Lymphocytes; Bacteria; Cancer Etiology; Cancer Vaccines; Cells; Cessation of life; Clinic; Clinical; DNA; DNA Methylation; Data; Decitabine; Dendritic Cells; Desmoplastic; Detection; Development; Early treatment; Engineering; Environment; Epigenetic Process; Epithelial; Exposure to; Flow Cytometry; Gene Expression; Genes; Genetic; Genetic Engineering; Genetically Engineered Mouse; Hematopoietic; Human; Human Papillomavirus; Immune; Immune Targeting; Immune response; Immune system; Immunohistochemistry; Immunosuppressive Agents; Immunotherapy; In Situ Hybridization; Individual; Inflammation; Inflammatory; Intervention; Intraepithelial Neoplasia; Lead; Learning; Lesion; Life Expectancy; Listeria monocytogenes; Lymphocyte; Lymphoid Cell; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of pancreas; Maps; Mediating; Methylation; Modality; Mus; Mutate; Mutation; Myelogenous; Normal tissue morphology; Oncogenes; Organ; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Premalignant; Prevention; Primary Prevention; Process; Proteins; Refractory; Risk; Satellite Viruses; Signal Pathway; Somatic Mutation; Staging; Stromal Cells; T cell response; Teenagers; Testing; Therapeutic; Therapeutic Intervention; Time; Vaccinated; Vaccination; Vaccines; Virus; Work; antitumor effect; cancer cell; cancer initiation; cancer prevention; cell type; cytokine; gene product; macrophage; mouse model; neoplastic cell; prevent; programs; public health relevance; response; screening; standard of care; tumor

DESCRIPTION (provided by applicant): The immune system recognizes small protein differences between cancer cells and the normal tissue from which they derive. Immunotherapy (cancer vaccines and immune modulators) is an emerging modality that educates the immune system to recognize these differences. Most cancers are insidious in their initiation, and develop over 10 to 30 years making it difficult to know when best to vaccinate and for how long. With recent advances mapping the genetic and epigenetic changes in cancers, it is now possible to apply principles learned from virus-targeted vaccines to the development of immunotherapies targeting the pathways induced by early genetic changes (driver genes) that are critical to cancer initiation. Cancers develop through a long process involving interconnections between genetic, epigenetic, and inflammatory signaling pathways that are constantly changing within the target organ as cells transition from normal to pre-malignant, to invasive cancer. In pancreatic adenocarcinoma (PDAC), emerging evidence suggests that these early changes induce a tumor-tolerant (anti-inflammatory) immune environment that includes a desmoplastic fibroblastic component, as well as various types of immunosuppressive stromal cells that produce cytokines, which inhibit anticancer (pro-inflammatory) immune responses. In this application we will test the hypothesis that targeting mutated Kras, the first genetic alteration driving PDAC initiation, can reverse the progressive pro-carcinogenic tolerogenic polarization that is associated with premalignancy development and progression. Furthermore, we will test the mechanistic hypothesis that the suppressive cellular response is under epigenetic control, and that targeting mutated Kras together with agents that change the phenotypic polarity of one or more cell types responsible for this procarcinogenic progression, will lead to tumor regression. We will employ a mouse model genetically programmed to progress through three stages of premalignancy (pancreatic intraepithelial neoplasms (PanINs) of increasing grade) before developing invasive cancer. In Aim 1 we will identify and characterize the phenotype and function of procarcinogenic inflammatory cell populations that are initiated by mutated Kras before and after vaccination with Listeria monocytogenes (LM) bacteria genetically engineered to express mutated Kras (LM-Kras). In Aim 2 we will perform a genetic and epigenetic analysis of suppressive cell versus anti-PanIN immune populations isolated from mouse and human PanINs. In Aim 3 we will combine the LM-Kras vaccine with the DNA hypomethylating drug 5aza- dC (DAC) and test for a synergistic anti-tumor effect. This application has significant translational implications that will fulfill an important clinical need - primary prevention and ealy treatment of a deadly cancer. We expect that the findings will drive a "proof of principle" clinica trial in subjects followed in screening clinics who are at risk for developing PDAC.

描述（由申请人提供）：免疫系统识别癌细胞与其来源的正常组织之间的微小蛋白质差异。免疫疗法（癌症疫苗和免疫调节剂）是一种新兴的方式，可以教育免疫系统识别这些差异。大多数癌症的发生都是潜伏的，并且会持续 10 至 30 年，因此很难知道何时最好接种疫苗以及持续多长时间。随着最近在绘制癌症遗传和表观遗传变化方面取得的进展，现在可以将从病毒靶向疫苗中学到的原理应用于开发针对早期遗传变化（驱动基因）诱导的途径的免疫疗法，这些早期遗传变化对癌症的发生至关重要。癌症的发展经历了一个漫长的过程，涉及遗传、表观遗传和炎症信号传导途径之间的相互联系，随着细胞从正常细胞转变为癌前病变，再转变为侵袭性癌症，这些信号传导途径在靶器官内不断变化。在胰腺腺癌（PDAC）中，新出现的证据表明，这些早期变化会诱导肿瘤耐受（抗炎）免疫环境，其中包括促结缔组织增生性成纤维细胞成分，以及产生细胞因子的各种类型的免疫抑制基质细胞，从而抑制抗癌。促炎症）免疫反应。在本申请中，我们将测试以下假设：针对突变的 Kras（驱动 PDAC 启动的第一个基因改变）可以逆转与癌前发生和进展相关的渐进性致癌耐受极化。此外，我们将测试以下机制假设：抑制性细胞反应受到表观遗传控制，并且针对突变的 Kras 以及改变导致这种致癌进展的一种或多种细胞类型的表型极性的药物将导致肿瘤消退。我们将采用经过基因编程的小鼠模型，使其在发展为浸润性癌症之前经历三个癌前阶段（级别递增的胰腺上皮内肿瘤（PanIN））。在目标 1 中，我们将鉴定并表征在接种经过基因工程改造表达突变 Kras (LM-Kras) 的单核细胞增生李斯特菌 (LM) 细菌之前和之后，由突变 Kras 启动的致癌炎症细胞群的表型和功能。在目标 2 中，我们将对从小鼠和人类 PanIN 中分离出的抑制性细胞与抗 PanIN 免疫群体进行遗传和表观遗传学分析。在目标 3 中，我们将把 LM-Kras 疫苗与 DNA 低甲基化药物 5aza-dC (DAC) 结合起来，并测试协同抗肿瘤作用。该应用具有重大的转化意义，将满足重要的临床需求——致命癌症的一级预防和早期治疗。我们预计这些发现将推动对有 PDAC 风险的诊所筛查受试者进行“原理证明”临床试验。