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

项目总结/摘要 胰腺癌患者的预后是明确差。这部分是由于纤维化和 胰腺肿瘤的免疫抑制微环境，其作为胰腺肿瘤的物理屏障， 化疗和免疫疗法。肿瘤内的遗传改变可导致免疫系统的重塑， 环境通过不同的细胞机制。致癌性Kras基因突变是最常见的 在胰腺癌中发生遗传事件，随后是TP 53的转化性改变。使用两个鼠标 模型和人体样本，我们将描述胰腺癌免疫细胞组成的变化， 具有特定p53突变的肿瘤。我的建议将阐明p53的潜在细胞机制- 在胰腺癌的情况下，依赖性免疫细胞募集到肿瘤微环境。在 此外，我们将研究突变型p53作为免疫治疗抗性标记的潜力。 这一提议可以支持改变临床实践，作为肿瘤遗传组成的综合分析， 免疫谱可用于开发精确的免疫疗法。基于我的分子学背景 在遗传学方面，我计划研究肿瘤内基因改变与免疫系统之间的关系。我会 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 Dafna Bar-Sagi博士和乔治米勒博士的指导。Bar-Sagi博士，国际致癌Ras专家 和细胞生物学，已经培养了超过50人在研究生和研究生水平，在她30年， 学术界，并撰写了150多篇同行评审的手稿。米勒博士，纽约大学珀尔马特癌症研究所所长 中心的肿瘤免疫学计划，是一个很好的出版免疫学家，其研究已经形成了 四个独立的胰腺癌临床试验的基础。在我的训练过程中，我会发展出 在胰腺癌和免疫技术和原则的专业知识，接受指导， 专业发展，并与学术领袖合作。我的职业规划包括实验室 培训，与我的导师和共同导师定期会议，积极参加会议和正式的教学 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 胰腺癌研究的科学家和领导者。Diane Simeone博士，纽约大学胰腺癌主任 中心和世界著名的外科医生科学家，将提供宝贵的指导胰腺癌和博士。 保罗奥伯斯坦，我们的胃肠肿瘤医学组主席，将帮助我的研究在一个 翻译语境血液科及肿瘤科主任黄国健医生是一位成功的 临床科学家，拥有一个发表良好的实验室，使用临床前模型研究临床治疗学。 NYU Langone Health拥有致力于胰腺癌的强大科学和临床项目，使其成为 世界领袖。我将受益于与临床和/或基础科学的许多杰出教师的互动 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.