Home page of Yimao Zhang

Background and interests
The major problem in cancer treatment is cancer metastasis and cancer remission, and cancer stem cells are thought to be the seeds of them. Surgery, chemotherapy and radiotherapy can remove almost all cell mass of a tumor, but cancers still regress, become resistant to drugs, spread out, and eventually kill patients. Multidrug resistance (MDR) has been found associated with overexpression of ATP-binding cassette (ABC) transporters, a family of proteins that use the energy of ATP hydrolysis to actively transport chemicals out of cells. There are three ABC transporters that have been found primarily associated with MDR, ABCB1 (Pgp), ABCC1 (MRP1), and ABCG2. Among them, ABCG2 is the one that has been found primarily responsible for the side population (SP) that is highly enriched with stem cells in both normal tissue and different cancer types, and has been indicated in the protection of stem cells from toxins. ABCG2 has a wide substrate spectrum, and has been found affecting the oral availabilty of its substrate drugs. Therefore, developing ABCG2 inhibitors to block the function of ABCG2 may have important clinic significance. Yet there is no ABCG2 inhibitor clinically available.

I have found that D-luciferin, the substrate of firefly luciferase (fLuc), is a specific substrate for ABCG2. FLuc is a commonly used reporter in bioluminescence imaging (BLI), and catalyzes the oxygenation of D-luciferin and releases photons, which can be quantified. When D-luciferin is applied to cells expressing fLuc, ABCG2 inhibitors, such as FTC, block the export of D-luciferin and increase effective intracellular D-luciferin that is accessible to fLuc, and cause enhanced light output. BLI is a very popular imaging technique, has extremely high signal-background ratio, and is very easy to use. Therefore, exploiting the fact to develop a BLI based high-throughput assay to screen for ABCG2 inhibitors can be very advantageous.

My current research direction is to use this novel BLI based high-throughput assay to screen for ABCG2 inhibitors and test the potential of the positive hits for research and clinical use.

Zhang Y, Youngjoo Byun, Yunzhao R. Ren, Jun O. Liu, J. Laterra, and M. Pomper. 2009. Identification of inhibitors of ABCG2 by a bioluminescence imaging-based high-throughput assay. Cancer Res. 69: 5867-5875.
Zhang Y, J. Laterra, and M. Pomper. 2008. The Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp. Neoplasia. 11(1): 96-101.
M. Pomper, Zhang Y, Laterra J. D-Luciferin-based Bioluminescence Resonance Energy Transfer (BRET) fusion reporter knock-in mouse for evaluation of ABCG2/BCRP expression and the pharmacokinetics of ABCG2/BCRP modulators in vivo. US patent application submitted, 2007.
M. Pomper, Zhang Y, Laterra J. High-throughput bioluminescence imaging for inhibitors of ABCG2/BCRP. US patent application submitted, 2007.
Zhang Y, J. Bressler, J. Neal, B. Lai, H. Bhang, J. Laterra, and M. Pomper. 2007. ABCG2/BCRP expression modulates D-luciferin-based bioluminescence imaging. Cancer Res, 67: 9389-9397.
Zhang, Y., J. Laterra, and M. Pomper. 2005. Imaging Modulation of Hedgehog Signaling in Vivo. Molecular Imaging. 4(3): 299 [abstract].
Zhang, Y., B. Lal, T. Reznik, J. Laterra, and M. Pomper. 2004. Imaging the Hedgehog Signaling Pathway. Molecular Imaging. 3: 256-7 [abstract].
Zhang, Y., S. Michaelis, and J.L. Brodsky. 2002. CFTR Expression and ER Associated Degradation in Yeast.CFTR expression and ER-associated degradation in yeast. Methods in Molecular Medicine. 70: 257-65.
Zhang, Y., G. Nijbroek, M. L. Sullivan, A. A. McCracken, S. C. Watkins, S. Michaelis, J. L. Brodsky. 2001. The Hsp70 molecular chaperone facilitates the ER associated protein degradation of the cystic fibrosis transmembrane conductance regulator in yeast. Molecular Biology of the Cell. 12 (5): 1303-1314.
Zhang, Y., and D. Zhao. 1997. The Molecular Biology of Drosophila Oogenesis. Chinese Journal of Cell Biology. 19(1): 9-17.