My lab has sought to translate our basic science discoveries to pre-clinical and clinical therapeutic development for brain cancers. Accomplishment is highlighted by the start of Phase I trial with a MELK inhibitor OTS167 for malignant solid cancers (NCT01910545) in 2014. We have nailed down the molecular mechanisms, with which MELK regulates GSC stemness and therapy resistance and identified handful anti-MELK inhibitors as leads for drug development.
a. Maternal embryonic leucine zipper kinase (MELK) is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. Nakano I, Saigusa K, Masterman-Smith M, Horvath S, Watanabe M, Negro A, Paucar AA, Lelievre V, Waschek JA, Lazareff JA, Freije WA, Liau LM, Gilbertson RJ, Cloughesy T, Geschwind DH, Nelson SF, Mischel PS, Tesrskikh A, Kornblum HI. J Neurosci Res 2007 Aug 24;86(1):48-60
b. Tumor-specific activation of the c-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Gu C, Banasavadi-Siddegowda YK, Joshi K, Nakamura Y, Kurt H, Gupta S, and Nakano I. Stem Cells 2013 Jan 17. doi: 10.1002/stem.1322. PMID: 23339114
c. MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Joshi K, Banasavadi-Siddegowda Y, Mo X, Kim S, Mao P, Kig C, Nardini D, Sobol RW, Chow L, Kornblum HI, Waclaw R, Beullens M, and Nakano I. Stem Cells 2013 Feb 13. doi: 10.1002/stem.1358. PMID: 23404835
d. Phosphorylation of a Polycomb component EZH2 by AKT activates STAT3 and promotes self-renewal and tumorigenicity of glioblastoma stem-like cells. Kim E, Kim M, ShinY, Joo KM, Woo DH, Chang N, Oh Y, Rheey J, Nakano I, Rich JN, Nam DH, Lee J. Cancer Cell 2013 Jun 10;23(6):839-52 PMID: 23684459
e. EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner. Kim SH, Joshi K, Ezhilarasan R, Myers TR, Siu J, Gu C, Nakano-Okuno M, Taylor D, Minata M, Sulman EP, Lee J, Bhat KP, Salcini AE, and Nakano I. Stem Cell Reports 2015 [in press]