Investigating the non-cell autonomous immune effects of mutant p53 in pancreatic cancer

研究突变型 p53 对胰腺癌的非细胞自主免疫作用

• 批准号: 10472325
• 负责人: Despina Siolas
• 金额: $ 22.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472325
• 关键词: 3-Dimensional; Academia; Advisory Committees; Affect; Basic Science; Biological; CXCL5 gene; Cancer Center; Cell physiology; Cells; Cellular biology; Clinical; Clinical Sciences; Clinical Treatment; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combination Drug Therapy; DNA Binding Domain; DNA Sequence Alteration; Development; Disease; Ductal Epithelial Cell; Embryo; Engineering; Environment; Event; Faculty; Fibroblasts; Flow Cytometry; Gene Expression Profile; Gene Mutation; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Health; Hematology; Human; Immune; Immune Tolerance; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunologic Techniques; Immunologist; Immunotherapy; Implant; Individual; International; KRAS oncogenesis; KRAS2 Gene Mutation; KRASG12D; Laboratory Study; Link; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Manuscripts; Medical Oncology; Mentors; Mentorship; Missense Mutation; Modality; Modeling; Molecular Genetics; Mus; Mutate; Mutation; Oncogenic; Oncology; Oncology Group; Paclitaxel; Pancreas; Pancreatic duct; Pattern; Peer Review; Phase II Clinical Trials; Phenotype; Physicians; Population; Pre-Clinical Model; Predisposition; Production; Prognosis; Program Development; Proteins; Publishing; Research; Resistance; Sampling; Scientist; Surgeon; T-Lymphocyte; TNFRSF5 gene; TP53 gene; Therapeutic Uses; Training; Treatment Efficacy; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Wild Type Mouse; Work; anticancer research; base; cancer cell; cancer therapy; career; chemokine; chemotherapy; clinical practice; combinatorial; cytokine; cytotoxic; experience; gain of function; gastrointestinal; gemcitabine; genetic makeup; in vivo; laboratory experience; macrophage; meetings; melanoma; mouse model; mutant; neoplastic cell; neutrophil; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; personalized immunotherapy; prevent; programs; recruit; resistance mechanism; symposium; therapeutic target; therapy resistant; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions; two-dimensional

Project Summary/Abstract The prognosis for pancreatic cancer patients is unequivocally poor. This is due in part to the fibrotic and immunosuppressive microenvironment of pancreatic tumors, which serves as a physical barrier to chemotherapy and immunotherapy. Intratumoral genetic alterations can cause remodeling of the immune environment through distinct cellular mechanisms. Oncogenic Kras gene mutations are the most frequently occurring genetic event in pancreatic cancer, followed by transforming alterations in TP53. Using both mouse models and human samples, we will characterize the changes in the immune cell composition of pancreatic tumors with specific p53 mutations. My proposal will delineate the underlying cellular mechanism of p53- dependent immune cell recruitment to the tumor microenvironment in the context of pancreatic cancer. In addition, we will investigate the potential of mutant p53 to serve as a marker of resistance to immunotherapy. This proposal could support changing clinical practice as integrated analysis of tumor genetic makeup and immune profiles may be used to develop precision immunotherapy. Building on my background in molecular genetics, I plan to study the relationship between intra-tumoral gene alterations and the immune system. I will need training in pancreatic cancer, immunology and cell biology and have decided to study under the mentorship of Dr. Dafna Bar-Sagi and Dr. George Miller. Dr. Bar-Sagi, an international expert in oncogenic Ras and cell biology, has trained over 50 individuals at the graduate and post-graduate level over her 30 years in academia and has authored over 150 peer-reviewed manuscripts. Dr. Miller, leader of NYU Perlmutter Cancer Center’s Tumor Immunology Program, is a well published immunologist whose research has formed the basis for four separate clinical trials in pancreatic cancer. Over the course of my training, I will develop expertise in pancreatic cancer and immunological techniques and principles, receive mentorship in professional development and collaborate with academic leaders. My career plan consists of laboratory training, regular meetings with my mentor and co-mentor, active conference participation and formal didactic coursework. My advisory committee will help me attain my goal of becoming an independent physician scientist and leader in pancreatic cancer research. Dr. Diane Simeone, Director of the NYU Pancreatic Cancer Center and world-renowned surgeon scientist, will provide valuable guidance on pancreatic cancer and Dr. Paul Oberstein, chair of our Gastrointestinal Medical Oncology Group, will help place my studies in a translational context. Dr. Kwok-Kin Wong, Director of the Division of Hematology and Oncology, is a successful clinician scientist with a well published laboratory that studies clinical therapeutics using pre-clinical models. NYU Langone Health has robust scientific and clinical programs dedicated to pancreatic cancer, making it a world leader. I will benefit from interacting with the many prominent faculty with clinical and/or basic science research experience, professional development programs and world class facilities.

项目摘要/摘要 胰腺癌患者的预后明确较差。这部分是由于纤维化和 胰腺肿瘤的免疫抑制微环境，作为物理障碍 化学疗法和免疫疗法。肿瘤内遗传改变会导致免疫的重塑 通过不同的细胞机制环境。致癌性KRAS基因突变是最常见的 发生在胰腺癌中的遗传事件，然后改变TP53的改变。使用两种鼠标 模型和人类样品，我们将表征胰腺免疫细胞组成的变化 具有特定p53突变的肿瘤。我的建议将描述p53-的潜在细胞机制 在胰腺癌的背景下，依赖性免疫细胞募集到肿瘤微环境。在 此外，我们将研究突变体p53作为对免疫疗法抗性的标志物的潜力。 该建议可以支持改变临床实践，作为对肿瘤遗传构成的综合分析和 免疫特征可用于开发精确的免疫疗法。在我的分子背景下建立 遗传学，我计划研究肿瘤内基因改变与免疫系统之间的关系。我会 需要在胰腺癌，免疫学和细胞生物学方面进行培训，并决定在 Dafna Bar-Sagi博士和George Miller博士的遗产。 Bar-Sagi博士，国际致癌RAS专家 和Cell Biology，在她30年的时间里已经在研究生和研究生水平上培训了50多名 Academia，并撰写了150多个同行评审的手稿。纽约大学Perlmutter癌症的负责人Miller博士 中心的肿瘤免疫学计划是一位发表良好的免疫学家，其研究成立了 在胰腺癌中进行四项独立的临床试验的基础。在我的培训过程中，我会发展 胰腺癌和免疫技术和原理方面的专业知识，接受心态 专业发展并与学术领导者合作。我的职业计划包括实验室 培训，与我的心理和同事的定期会议，积极的会议参与以及正式教学 课程。我的咨询委员会将帮助我实现成为独立医生的目标 胰腺癌研究的科学家和领导者。纽约大学胰腺癌主任黛安·西蒙内（Diane Simeone）博士 中心和世界著名的外科医生科学家将为胰腺癌提供宝贵的指导和博士。 我们胃肠道医学肿瘤学小组主席保罗·奥伯斯坦（Paul Oberstein）将帮助我的学习 翻译环境。血液学和肿瘤学系主任Kwok-Kin Wong博士是一个成功的 临床科学家的出版良好的实验室，该实验室使用临床前模型研究临床治疗。 NYU Langone Health拥有致力于胰腺癌的强大科学和临床计划，使其成为 世界领导人。与临床和/或基础科学的许多著名教师互动，我将受益 研究经验，专业发展计划和世界一流的设施。