External MBB Seminar: Prof. Klas Wiman
Speaker: Prof. Klas Wiman (Prof. of Molecular Cell and Tumor Biology at the Dept. of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet)
Title: “Mutant p53 reactivation by small molecules - from lab bench to clinical trials”
Host: Tomas Nyman, Protein Science Facility
Prof. Wiman’s laboratory focuses on the tumor suppressor gene p53 and the p53-regulated gene Wig-1/Zmat3. The p53 gene has a key role as trigger of cell cycle arrest or cell death upon oncogenic stress. Many types of human cancer carry p53 missense mutations that result in expression of high levels of dysfunctional p53 protein. Work in Wiman’s lab has led to the identification of small molecules that can rescue mutant p53. One such molecule, APR-246 has been tested in a Phase I/II clinical trial with promising results.
- Restoration of the tumor suppressor function to mutant p53 by a low molecular weight compound. Bykov, V.J. et al. Nature Med. 8, 282-8, 2002.
- Shaping genetic alterations in human cancer: the p53 mutation paradigm. Soussi, T., and Wiman, K.G. Cancer Cell 12, 303-12, 2007
- 3. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Lambert, J.M.R. et al. Cancer Cell 15, 376-88, 2009.
- 4. The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element. Vilborg, A. et al. Proc. Natl. Acad. Sci. USA 106, 15756-61, 2009.
- Targeting p53 in vivo: A first-in-man study with the p53-targeting compound APR-246 in refractory hematological malignancies and prostate cancer. Lehmann, S. et al. Clin. Oncol. 30, 3633-9, 2012.