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

项目摘要/摘要 胰腺癌患者的预后无疑是很差的。这在一定程度上是由于纤维化和 胰腺肿瘤的免疫抑制微环境，这是对 化疗和免疫治疗。肿瘤内基因改变可导致免疫重塑 通过不同的细胞机制影响环境。致癌的kras基因突变是最常见的 在胰腺癌中发生遗传事件，随后在TP53发生转化改变。同时使用两个鼠标 模型和人体样本，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。我的提案将描述p53的潜在细胞机制- 胰腺癌背景下依赖免疫细胞向肿瘤微环境的募集。在……里面 此外，我们还将研究突变型P53作为免疫治疗耐药标志物的可能性。 这项建议可以支持改变临床实践，因为综合分析肿瘤基因组成和 免疫图谱可能被用于开发精确的免疫疗法。以我的分子专业背景为基础 遗传学方面，我计划研究肿瘤内基因改变与免疫系统之间的关系。这就做 需要接受胰腺癌、免疫学和细胞生物学方面的培训，并决定在 达夫纳·巴尔-萨吉博士和乔治·米勒博士的指导。巴尔-萨吉博士，致癌RAS的国际专家 和细胞生物学，在她30年的时间里，已经培训了50多个研究生和研究生 并撰写了150多篇同行评议的手稿。米勒博士，纽约大学珀尔穆特癌症中心的负责人 中心的肿瘤免疫学项目，是一位出版良好的免疫学家，他的研究形成了 四项单独的胰腺癌临床试验的基础。在我的训练过程中，我将会发展 在胰腺癌和免疫学技术和原理方面的专业知识，在 专业发展，并与学术领袖合作。我的职业生涯规划包括实验室 培训，定期与我的导师和合作导师会面，积极参加会议和正式授课 课程作业。我的顾问委员会将帮助我实现成为一名独立医生的目标 科学家和胰腺癌研究的领导者。Diane Simeone博士，纽约大学胰腺癌主任 该中心和世界知名外科科学家将为胰腺癌和Dr。 保罗·奥伯斯坦，我们胃肠道医学肿瘤学小组的主席，将帮助我的研究在 翻译语境。血液和肿瘤科主任王国健医生是一位成功的 临床科学家，拥有一家出版广泛的实验室，使用临床前模型研究临床疗法。 纽约大学朗格尼健康中心拥有强大的科学和临床项目，致力于胰腺癌，使其成为 世界领袖。我将从与许多临床和/或基础科学方面的杰出教员的互动中受益。 研究经验、专业发展计划和世界一流的设施。

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.