Wednesday, February 5, 2025
2/5/2025
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.
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