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The role of PI3K in pancreatic cancer genetics and progression

PI3K 在胰腺癌遗传学和进展中的作用

基本信息

批准号：
10266023
负责人：
RICHARD Z LIN
金额：
--
依托单位：
NORTHPORT VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266023
关键词：
Ablation Adoptive Transfer Affect Animals Antigens Biological Assay C57BL/6 Mouse CD8B1 gene CRISPR/Cas technology Cancer Etiology Catalytic Domain Cell Line Cells Cessation of life Chemotherapy and/or radiation Complex Control Groups Cytotoxic T-Lymphocytes Disease Down-Regulation Drug resistance Excision Exhibits Exposure to Future Genes Genetic Goals Harvest Human Immune Immune Evasion Immune response Immune system Immunocompetent Immunodeficient Mouse Immunologic Surveillance Immunologics Immunology Implant In Vitro KRASG12D Knock-out Lentivirus MHC Class I Genes Malignant Neoplasms Malignant neoplasm of pancreas Masks Mediating Molecular Monitor Mus Mutation Names Normal tissue morphology Oncogenic Operative Surgical Procedures Outcome Pancreas Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Pharmacology Phosphatidylinositols Phosphotransferases Play Population Protein Isoforms Radiation therapy Reporting Resistance Role SCID Mice Signal Pathway Signal Transduction Study models Survival Rate T cell response T cell therapy T-Lymphocyte Testing Therapeutic Tumor Cell Line Wild Type Mouse Work anti-cancer antitumor effect cancer genetics cytotoxic effective therapy exome sequencing experimental study genetic analysis implantation improved in vivo in vivo imaging system inhibitor/antagonist insight kinase inhibitor mortality mutant neoplastic cell new therapeutic target novel therapeutic intervention pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic neoplasm patient population side effect transcriptome sequencing tumor tumor growth tumor progression tumorigenesis

项目摘要

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the U.S.A., with a five-year survival rate of 4%. It is also a major cause of mortality among the VA patient population. There is great urgency to identify new therapeutic strategies for PDAC because current treatments have little impact on patient survival. More than 90% of PDACs have oncogenic mutations in the Kras gene. The phosphoinositide 3-kinase p110α catalytic subunit (gene name Pik3ca) is a downstream effector of Kras. We previously reported that pancreas-specific ablation of Pik3ca completely protected mice from oncogenic KrasG12D-induced tumor formation. The current proposal investigates the role of Pik3ca after pancreatic tumors have formed. Invasive KrasG12D and Trp53R172H (KPC) cells orthotopically implanted in the pancreas of immunocompetent mice leads to rapid tumor progression and death of the host animal. However, when Pik3ca was silenced, implanted KPC tumors completely regressed. Surprisingly, implanted Pik3ca-null KPC tumors progressed and killed immunodeficient mice, but adoptive transfer of T lymphocytes completely protected the mice from these tumors. Therefore, we hypothesize that inhibition of Pik3ca in the tumor cells, without inhibiting PI3K signaling in the immune cells, will allow an immune-mediated regression of pancreatic cancer. In Aim 1, we will investigate the signaling pathways and genetic profiles of Pik3ca-null versus parental KPC cells to better understand the immunological changes caused by the knockout tumor cells. We will also examine the host T-cell response to better understand how pancreatic tumors evade immune surveillance. In Aim 2, we will assess the therapeutic potential of a strategy that inhibits p110α in pancreatic cancer cells without inhibiting PI3K signaling in cytotoxic T lymphocytes. Successful completion of this proposal will produce insights into PI3K-regulated mechanisms that allow PDAC to evade the immune system and progress to a deadly disease. This understanding may allow future studies to elucidate the most appropriate means of targeting Pik3ca signaling pathways in PDAC to improve therapy for this deadly cancer.

胰腺导管腺癌（PDAC）是美国癌症相关死亡的第三大原因，五年存活率为4%它也是VA患者人群死亡的主要原因。由于目前的治疗方法缺乏有效的治疗手段，因此迫切需要确定PDAC的新治疗策略。影响患者生存。超过90%的PDAC在Kras基因中具有致癌突变。的磷酸肌醇3-激酶p110α催化亚基（基因名称Pik 3ca）是Kras的下游效应子。我们先前报道，胰腺特异性消融Pik 3ca完全保护小鼠免受致癌性 KrasG 12 D诱导的肿瘤形成。目前的提案调查了Pik 3ca在胰腺肿瘤后的作用已经形成。将侵袭性KrasG 12 D和Trp 53 R172 H（KPC）细胞原位植入小鼠的胰腺中，免疫活性小鼠的肿瘤转移导致宿主动物的快速肿瘤进展和死亡。当Pik 3ca 沉默，植入的KPC肿瘤完全消退。令人惊讶的是，植入的Pik 3ca-无效KPC肿瘤进展并杀死了免疫缺陷小鼠，但过继转移的T淋巴细胞完全保护了免疫缺陷小鼠。从这些肿瘤中分离出来。因此，我们假设在肿瘤细胞中抑制Pik 3ca，而不抑制免疫细胞中的PI 3 K信号传导将允许免疫介导的胰腺癌消退。在目标1中，我们将研究Pik 3ca-null与亲本KPC的信号通路和遗传特征。细胞，以更好地了解由敲除肿瘤细胞引起的免疫学变化。我们还将检查宿主T细胞反应，以更好地了解胰腺肿瘤如何逃避免疫监视。在目的2，我们将评估抑制胰腺癌细胞中p110α的策略的治疗潜力而不抑制细胞毒性T淋巴细胞中的PI 3 K信号传导。成功完成此提案将深入了解PI 3 K调节机制，使PDAC逃避免疫系统并进展一种致命的疾病。这种理解可能使未来的研究能够阐明最适当的方法，靶向PDAC中的Pik 3ca信号通路，以改善这种致命癌症的治疗。