The 10th International MDM2 Workshop

第十届国际MDM2研讨会

基本信息

批准号：
10814471
负责人：
Tomoo Iwakuma
金额：
$ 1.5万
依托单位：
CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10814471
关键词：
Acetylation African American Antineoplastic Agents Apoptosis Area Award Basic Science Binding Biology COVID-19 Cancer Biology Cancer Center Career Mobility Cell Cycle Progression Child Cities Clinical Research Clinical Trials Collaborations Communities Complex DNA Repair Doctor of Philosophy Drug Industry Drug Targeting Educational workshop Ensure Europe Event Florida Funding Gene Deletion Gene Mutation Genes Genetic Transcription Goals Grant Hispanic Homologous Gene Human Immunity In Vitro Individual International Japan Location MDM2 Gene Amplification MDM2 gene Malignant Neoplasms Mediating Medicine Mentors Minority Mutate NCI Center for Cancer Research New York Oncogenic Participant Pathway interactions Pharmaceutical Preparations Phosphorylation Play Postdoctoral Fellow Proteins Public Health Reagent Regulation Research Research Institute Research Personnel Role Scientist Senior Scientist Signal Transduction Singapore Students TP53 gene Tokyo Translational Research Travel Tumor Suppressor Proteins Ubiquitination Underrepresented Minority Underrepresented Populations United Kingdom United States Universities Up-Regulation Woman Writing anti-PD-L1 anticancer research cancer immunotherapy career clinically relevant college design drug discovery graduate student in vivo inhibitor interdisciplinary approach man medical schools meetings mouse model overexpression patient subsets public health relevance response social tumor ubiquitin-protein ligase

项目摘要

Project Summary/Abstract The p53 protein is the most frequently mutated gene in human cancers and functions as a tumor suppressor by transcriptionally regulating numerous downstream target genes involved in cell cycle progression and apoptosis. MDM2 and its homolog MDM4 (also known as MDMX) are two of the most important negative regulators of p53 by acting as an E3 ubiquitin ligase complex to promote p53 degradation and by physical binding to inhibit the p53’s transcriptional function. These proteins are also overexpressed in approximately 30% of human cancers. Overexpression of MDM2/MDM4 not only inhibits p53 function, but also shows p53-independent oncogenic activities. Intriguingly, gene amplification of MDM2 and MDM4 is associated with adverse hyperprogressive response to anti-PDL1 cancer immunotherapy in a subset of patients. Thus, inhibitors for MDM2 and MDM4 have been developed to inhibit their oncogenic activities and to reactivate wild-type p53 in tumors. Importantly, some MDM2/MDM4 inhibitors are in clinical trials. The first International MDM2 Workshop, held in 2001 in the United Kingdom, was primarily in response to a significant increase in the research related to p53 and its negative regulators MDM2/MDM4, as well as strong demand for drug discovery targeting MDM2/MDM4/p53. The expansion of the scientific community studying MDM2/MDM4 and the need to pursue this area of research with a collaborative multidisciplinary approach have further made the MDM2 Workshop necessary. The MDM2 Workshop is held every two or three years, at locations alternating between the United States and Europe, to bring together the p53/MDM2 field, present the latest research, and facilitate collaboration and exchange of reagents. Indeed, both the p53 and MDM2 Workshops have become important platforms for long-term scientific exchange and new investigators of the MDM2-p53 pathway. The 10th International MDM2 Workshop will be held at an auditorium of the newly built National Cancer Center Research Institute (NCCRI) in Tokyo, Japan, on October 15-18, 2023. This will be the first International p53/MDM2 Workshop organized and held in Japan. The meeting will be co-organized by Dr. Rieko Ohki (NCCRI, Tokyo, Japan), Dr. Koji Itahana (Duke-NUS Medical School, Singapore), and Dr. Tomoo Iwakuma (Children’s Mercy Research Institute, MO, USA). Notably, due to COVID-19, we have not had the MDM2 Workshop for over 4 years, since the 9th MDM2 Workshop on November 4-7, 2018 in Florida. We expect more participants with higher enthusiasm for this 10th MDM2 Workshop, as compared with the previous MDM2 Workshops. Significant numbers of US researchers, including the international organizing committee (11 out of 16, 38% women), are expected to participate in and benefit from the meeting. Hence, we are applying for R13 funding to support this important and exciting international meeting that will energize research in US and promote scientific progress and interactions in the p53/MDM2 field. Funds are requested to support three important specific aims designed to promote participation of the US investigators and trainees.

项目概要/摘要 p53 蛋白是人类癌症中最常突变的基因，通过以下方式发挥肿瘤抑制因子的作用：转录调节参与细胞周期进程和细胞凋亡的众多下游靶基因。 MDM2 及其同源物 MDM4（也称为 MDMX）是 p53 的两个最重要的负调节因子通过充当 E3 泛素连接酶复合物促进 p53 降解并通过物理结合抑制 p53 的转录功能在大约 30% 的人类癌症中也过度表达。 MDM2/MDM4 的过度表达不仅抑制 p53 功能，而且显示出 p53 独立的致癌作用有趣的是，MDM2 和 MDM4 的基因扩增与不良的超进展有关。因此，MDM2 和 MDM4 抑制剂对部分患者的抗 PDL1 癌症免疫治疗有反应。已被开发用于抑制其致癌活性并重新激活肿瘤中的野生型 p53。一些MDM2/MDM4抑制剂正在进行临床试验第一届国际MDM2研讨会于2001年举行。英国，主要是为了应对 p53 相关研究的显着增加及其负面影响 MDM2/MDM4 调节因子，以及针对 MDM2/MDM4/p53 的药物发现的强烈需求。研究 MDM2/MDM4 的科学界的扩大以及开展这一领域研究的必要性多学科协作方法进一步使得 MDM2 研讨会变得必要。研讨会每两三年举办一次，地点在美国和欧洲交替举行，以汇聚p53/MDM2领域，展示最新研究成果，促进合作交流事实上，p53 和 MDM2 研讨会都已成为长期科学的重要平台。 MDM2-p53途径的交流和新研究者将举行第十届国际MDM2研讨会。在日本东京新建的国家癌症中心研究所 (NCCRI) 的礼堂 2023 年 10 月 15 日至 18 日。这将是在日本组织和举办的首届国际 p53/MDM2 研讨会。会议将由 Rieko Ohki 博士（NCCRI，日本东京）和 Koji Itahana 博士（Duke-NUS Medical 学校，新加坡）和 Tomoo Iwakuma 博士（美国密苏里州儿童慈善研究所）。 COVID-19，自 11 月举办第九届 MDM2 研讨会以来，我们已经有 4 年多没有举办 MDM2 研讨会了 2018 年 4-7 日在佛罗里达州举行，我们期待更多的参与者以更高的热情参加第十届 MDM2 研讨会。与之前的 MDM2 研讨会相比，有大量的美国研究人员，包括国际组委会（16 人中有 11 人，其中 38% 为女性）预计将参与并受益因此，我们正在申请 R13 资金来支持这次重要且令人兴奋的国际会议。这将激励美国的研究并促进 p53/MDM2 基金领域的科学进步和互动。要求支持旨在促进美国调查人员参与的三个重要具体目标和实习生。