There is emerging evidence showing that a small population of cancer stem cells (CSCs) within cancers is responsible for tumor formation. Recent published data also showed that medulloblastoma (MB) and glioblastoma (GBM) contain such CSCs. The CSC hypothesis challenges traditional therapeutic concepts, suggesting that only by removing CSCs within a tumor can the cancer be cured. Our goal is to develop novel therapies for the malignant brain tumors MB and GBM based on the depletion of CSCs. It has been shown that the Notch singling pathway regulates normal stem cells in the central nervous system (CNS), and that MB and GBM contain CSCs with higher Notch activity. We have demonstrated recently that Notch pathway inhibition by gamma-secretase inhibitor (GSI) depletes CSCs and blocks engraftment in MB and GBM both in vitro and in vivo. This work represents a strong demonstration of a chemotherapeutic agent that can target CSC in solid tumors. A recent Phase I clinical trial study (2012) shows that 24% of glioma patients have prolonged stable disease upon GSI treatment.
Our current projects include examining the mechanism by which Notch, SHH, and Wnt signaling pathways and microRNAs that regulate these brain CSCs, and investigating the interaction between CSCs and their niche. The ongoing projects (09/01/2011 – 07/31/2017) are supported by two NIH R01 grants (R01CA148621 and R01CA163737). These studies will help develop novel therapies for these deadly diseases.
1. Zhu TS, Costello MA, Talsma CE, Flack CG, Crowley JG, Hamm LL, He X, Hervey-Jumper SL, Heth JA, Muraszko KM, DiMeco F, Vescovi AL, and Fan X*. Endothelial cells create a stem cell niche in glioblastoma by providing Notch ligands that nurture self-renewal of cancer stem-like cells.
Cancer Research, Sep 15;71(18):6061-72, 2011. (*: Corresponding Author).
2, Fan X*, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciaczyk J, Nikkhah G, DiMeco F, Piccirillo S, Vescovi AL, Eberhart CG. Notch Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts.
Stem Cells, Jan;28(1):5-16, 2010. (*: Corresponding Author).
3, Fan X*, Eberhart CG*. Medulloblastoma Stem Cells.
Journal of Clinical Oncology, Jun 10;26(17):2821-7, 2008. (*: Corresponding Author)
4, Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, Eberhart CG. Notch Pathway Inhibition Depletes Stem-Like Cells and Blocks Engraftment in Embryonal Brain Tumors.
Cancer Research, August 1; 66(15):7445-52, 2006.
5, Dang L, Fan X (co-first author), Chaudhry A, Wang M, Gaiano N, Eberhart CG. Notch3 Signaling Initiates Choroid Plexus Tumor Formation.
Oncogene, Jan 19;25(3):487-91, 2006.
6, Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, Brat DJ, Perry A, Eberhart CG. Notch1 and Notch2 have opposite effects on embryonal brain tumor growth.
Cancer Research, Nov 1;64 (21):7787-93, 2004. (Featured on cover).
7, Fan X, Wang Y, Kratz J, Brat DJ, Robitaille Y, Moghrabi A, Perlman EJ, Dang CV, Burger PC, Eberhart CG. hTERT gene amplification and increased mRNA expression in central nervous system embryonal tumors.
American Journal of Pathology, Jun;162 (6):1763-9, 2003.