Research Interests:
Ubiquitin E3 ligases E3 ligase inhibitors Cancer Therapeutics Combination therapiesAbout Xinjiang Wang
Biography:
Xinjiang Wang, PhD, is currently Associate Professor of Oncology in Department of Pharmacology & Therapeutics at Roswell Park Comprehensive Cancer Center. Xinjiang joined Prof. Takeo Ohnishi’s lab as a visiting scientist in Department of Radiation Oncology at Nara Medical University, Nara, Japan (1994-1998) where he studies p53 signaling in response to low-dose and space radiation and to non-genotoxic stress such as heat shock, cold shock and low pH conditions. He received Master’s degree of Science Education from Nara University of Education under supervision of Prof. Kohta Suda and Prof. Ohnishi (1996-1998). In 1998, he left Japan for Israel to join Prof. Moshe Oren’s Lab for his PhD training (1998-2003) in the Department of Molecular Cell Biology at Weizmann Institute of Science, Rehovot, Israel. He studied nitric oxide signaling to p53 and posttranslational mechanisms by which MDM2 regulates tumor suppressor p53 activity. He obtained his PhD in Molecular Cell Biology in 2003.
In 2004, Xinjiang went to Memorial Sloan-Kettering Cancer Center (MSKCC), New York and joined Prof. Xuejun Jiang’s Lab (2004-2009) in the Department of Cancer Biology to conduct his postdoctoral research on regulation of tumor suppressor PTEN. In 2009, he joined the faculty as an Assistant Professor in the Department of Pharmacology & Therapeutics at Roswell Park Comprehensive Cancer Center.
Since 2009, Xinjiang’s lab has been using biochemical, molecular cell biology and genetic approaches to understanding of how oncogenic E3 ligases such as MDM2 and NEDD4 regulates its targets to promote cancerous growth. His lab has been interested in translating their discovery to cancer drug development. For example, they identified RING-RING interaction of heterodimer E3 ligase MDM2-MDM4 as a new targeting interface and identified a few lead compounds as RING domain inhibitors designated as MMRis that possess p53-independent antitumor effect. His lab is also interested in developing novel combination therapies for overcoming resistance to current therapies in leukemia/lymphoma, melanoma and pancreatic cancer.
Positions
- Associate Professor of Oncology
- Department of Pharmacology & Therapeutics
Background
Education and Training:
- 2009 - Post-doctoral - Memorial Sloan-Kettering Cancer Center, New York, NY
- 2003 - PhD - Weizmann Institute of Science, Rehovot, Israel
- 1998 - M.Ed.- Science Education, Nara University of Education, Nara, Japan
Professional Memberships:
- American Association for Cancer Research
- American Society of Biochemistry and Molecular Biology (ASBMB)
Research
Research Overview:
Research Overview:
Our lab focuses on cancer relevant ubiquitin E3 ligases, a class of enzymes that regulate degradation of key oncoproteins and tumor suppressors. Identification of such E3 ligases and understanding of their mechanisms of action will pave a way for screening of small molecule compounds as novel therapies for cancer. Our current interests are in MDM2-MDM4 heterodimer E3 ligase and NEDD4-1. How to effectively target the oncogenic activity of MDM2-MDM4 and NEDD4-1 is of great interest in the field. Using biochemical approaches we identified RING-RING interaction of MDM2-MDM4 is essential for their E3 ligase activity to promote polyubiquitination and degradation of tumor suppressor p53. Using genetically engineered mouse models we concluded that the E3 ligase activity of MDM2-MDM4 heterodimers is not only required for p53 regulation and but also for cell cycle integrity independent of p53. To translate our discoveries from basic research to cancer medicine, we identified several lead compounds (MMRi) that target RING-RING interaction of MDM2-MDM4. For example, MMRi62 showed anti-tumor effect in vitro and in vivo. One advantage of MMRi62 is its cell death induction independent of p53 status, which is useful for targeting late-stage and p53-mutant cancers often resistant to current therapies. Another interesting property of MMRi62 is the different modes of cell death in different cancers: apoptosis in leukemia/lymphoma cells and ferroptosis in pancreatic cancers possibly due to induced FTH1 degradation. Currently our lab is pursing the following directions.
1. Elucidation of mechanisms of action for MMRi62 in cell death induction.
2. Identification of biomarkers for the response to MMRi62 treatment in cancer.
3. Develop MMRi71-based combination therapies boosting cell death induction in solid tumors.
4. Optimization of MMRi62-like compounds suitable for clinical advancement.
Publications
Representative Publications:
- Chinnam M, Xu C, Lama R, Zhang X, Cedeno CD, Wang Y, Stablewski AB, Goodrich DW*, Wang X*. MDM2 E3 ligase activity is essential for p53 regulation and cell cycle integrity. PLoSGenet. 2022 May 19;18(5):e1010171. doi: 10.1371/journal.pgen.1010171. PMID: 35588102 PMCID: PMC9119546.
- Li J, Lama R, Galster SL, Inigo JR, Wu J, Chandra D, Chemler SR, Wang X*. Small-Molecule MMRi62 Induces Ferroptosis and Inhibits Metastasis in Pancreatic Cancer via Degradation of Ferritin Heavy Chain and Mutant p53. Mol Cancer Ther. 2022 Feb 7; doi: 10.1158/1535-7163. PMID: 35131878.
- Lama R, Xu C, Galster SL, Querol-García J, Portwood S, Mavis CK, Ruiz FM, Martin D, Wu J, Giorgi MC, Bargonetti J, Wang ES, Hernandez-Ilizaliturri FJ, Koudelka GB, Chemler SR, Muñoz IG, Wang X*. Small molecule MMRi62 targets MDM4 for degradation and induces leukemic cell apoptosis regardless of p53 status. Front. Oncol., Cancer Molecular Targets and Therapeutics, 05 August 2022. PMID: 35992795 PMCID: PMC9389462.
- Lama R, Galster SL, Xu C, Davison, LW, Chemler SR*, Wang X*. Dual Targeting MDM4 and FTH1 by Small-Molecule MMRi71 for Induced Protein Degradation and p53-independent Apoptosis in Leukemia Cells. Molecules 2022, 27(22), 7665. PMID: 36431769 PMCID: PMC9695299.
- Wu W, Xu C, Ling X, Fan CD, Buckley BP, Chernov MV, Ellis L, Li F, Munoz IG, Wang X*. Targeting RING domains of Mdm2-MdmX E3 Complex Activates Apoptotic Arm of the p53 pathway in Leukemia/lymphoma cells. Cell Death & Disease 2015, 6(12): e2035. PMCID: PMC472089. PMID: 26720344.
- Xu C, Fan CD, Wang X*. Regulation of Mdm2 Protein stability and the p53 response by NEDD4-1 E3 ligase. Oncogene 2014. Jan 13. doi: 10.1038/onc.2013.557. PMCID: PMID: 24413038
- Wang X*, Wang J, Jiang X. MDMX Protein is Essential for Mdm2 Protein-mediated p53 polyubiquitination. Journal of Biological Chemistry 2011; PMCID: PMC3129153.
- Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X. Nedd4-1 is the Proto-Oncogenic Ubiquitin Ligase for PTEN. Cell 2007; 128(1):129-139. PMCID: PMC1828909.
- Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, Pavletich NP, Carver BS, Cordon-Cardo C, Erdjument-Bromage H, Tempst P, Chi S-G, Kim H-J, Misteli T, Jiang X, Pandolfi PP. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 2007; 128(1):141-156. PMCID: PMC1855245.