Anti-Cancer Molecules Discovered by In Silico Small Molecule Screening (利用電腦小分子篩選發現抗癌分子)
Research Field
Associate Professor
2019-present
Chang Gung University, College of Medicine, Department of Biomedical Sciences, Kwei-Shan, Tao-Yuan, Taiwan ROC
Assistant Professor
2010-2019
Chang Gung University, College of Medicine, Department of Biomedical Sciences, Kwei-Shan, Tao-Yuan, Taiwan ROC
Lecturer
2016-present
The Beutler Institute, Xiamen University, Xiamen, China
2013-2016, 2023-present
Xiamen University, School of Life Sciences, Xiamen, China
Associate Research Fellow
2019-present
Division of Head & Neck Surgery, Department of Otolaryngology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
Assistant Research Fellow
2016-2018
Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan
Postdoctoral Fellow
2002-2009
Harvard University, Cambridge, MA Laboratory Director: Dr. Andrew W. Murray
Instructor
2004-2005
Harvard University Extension School, Cambridge, MA
Research Associate
2001-2002
Dana-Farber Cancer Institute, Boston, MA
Laboratory Director: Dr. David Pellman
Targeting APC/C-CDC20 to Enhance the Effectiveness of Paclitaxel and Anti-Cancer Drugs:
Cancers have been the leading cause of death in Taiwan and Japan for the past 42 and 44 years, respectively, and currently are responsible for about 1/6th of deaths globally. Our goal is to enhance the effectiveness of paclitaxel, which is FDA approved for the treatment of more than 20 types of adult cancers, and other anti-cancer drugs. The therapeutic index of 10 nM paclitaxel, the clinically relevant amount to work with in lab cultured MDA-MB-231 cell lines, is hypothesized not to involve cell cycle arrest in mitosis, but rather may be derived from the formation of multipolar mitotic spindles that can lead to two different cell death fates after a mother cell with a multipolar spindle executes an aberrant mitosis. First, elevated levels of chromosome mis-segregation on the multipolar spindle may induce necrosis/apoptosis/quiescence in the daughter cells. Second, a lagging chromosome(s) in anaphase on the multipolar spindle of the mother cell may lead to a chromatin bridge(s) in cytokinesis that activate the cyclic GMP–AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) pathway in the daughter cells which may promote type I interferon (IFN) secretion resulting in leukocyte recruitment into solid tumors which execute immunogenic cell death, a pathway that can also be activated during apoptosis and/or necrosis. The efficacy of paclitaxel has been enhanced by combinatorial therapies based on anti-immune checkpoint drugs targeting programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1). Many patients do not respond to paclitaxel treatments before critical limiting doses of paclitaxel are reached, caused by adverse side effects such as neutropenia, mucositis and/or neurotoxicity. Our approach is to specifically target the Anaphase-Promoting Complex/Cyclosome-Cell Division Cycle 20 (APC/C-CDC20) enzyme complex by in silico screening to identify small molecules that delay anaphase entry without inducing a mitotic cell cycle arrest which may enhance the effectiveness of paclitaxel and other anti-cancer drugs.
To enhance anti-mitotic and senolytic anti-cancer drugs, our approach is to specifically target the Anaphase-Promoting Complex/Cyclosome-Cell Division Cycle 20 (APC/C-CDC20) enzyme complex to try and delay anaphase entry without inducing a mitotic cell cycle arrest (Schuyler, et al, 2018; Schuyler and Chen, 2021). We speculate, for example, that delaying anaphase entry in the presence of 10 nM paclitaxel, the clinically relevant amount, may decrease multipolar spindles in genomically stable healthy cells and increase multipolar spindle formation in genomically unstable cancer cells. Levels of multipolar spindles induced by 10 nM paclitaxel have been observed to decrease from prophase to metaphase in genomically stable CAL-51 cells, and have also been observed to decrease from metaphase into anaphase in genomically stable CAL-51, RPE-1 and MCF-10A cells, while, by contrast, in genomically unstable cells, like MDA-MB-231 and HeLa cells, the levels of multipolar spindles have been observed to increase from metaphase into anaphase (Scribano, et al., 2021). Healthy human cells have been selected to be genomically stable (Knouse, et al., 2014; Liu, et al., 2022), while cancer cells have been selected to be genomically unstable resulting in aneuploidy (Weaver and Cleveland, 2006). Thus, in the presence of 10 nM paclitaxel, a delay in anaphase entry may give genomically stable cells more time to repair their spindles, while genomically unstable cells delayed in anaphase entry may display an increase in multipolar spindles in anaphase, which will promote cancer cell death.
References:
Knouse, KA, Wu, J, Whittaker, CA, Amon, A. (2014). Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A. Sep 16;111(37):13409-14. doi: 10.1073/pnas.1415287111. Epub 2014 Sep 2.
Liu, L, Chen, H, Sun, C, Zhang, J, Wang, J, Du, M, Li, J, Di, L, Shen, J, Geng, S, Pang ,Y, Luo, Y, Wu, C, Fu, Y, Zheng, Z, Wang, J, Huang Y. (2022). Low-frequency somatic copy number alterations in normal human lymphocytes revealed by large-scale single-cell whole-genome profiling. Genome Res. Jan;32(1):44-54. doi: 10.1101/gr.275453.121. Epub 2021 Dec 28.
Schuyler, SC, Wu, YO, Chen, HY, Ding, YS, Lin, CJ, Chu, YT, Chen, TC, Liao, L, Tsai, WW, Huang, A, Wang, LI, Liao, TW, Jhuo, JH, Cheng, V. (2018). Peptide inhibitors of the anaphase promoting-complex that cause sensitivity to microtubule poison. PLoS One. Jun 8;13(6):e0198930. doi: 10.1371/journal.pone.0198930.
Schuyler, SC and Chen HY. (2021) Using budding yeast to identify molecules that block cancer cell ‘mitotic slippage’ only in the presence of mitotic poisons. Int. J. Mol. Sci. 22, 7985.
Scribano, CM, Wan, J, Esbona, K, Tucker, JB, Lasek, A, Zhou, AS, Zasadil, LM, Molini, R, Fitzgerald, J, Lager, AM, Laffin, JJ, Correia-Staudt, K, Wisinski, KB, Tevaarwerk, AJ, O'Regan, R, McGregor, SM, Fowler, AM, Chappell, RJ, Bugni, TS, Burkard, ME, Weaver, BA. (2021). Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel. Sci Transl Med. Sep 8;13(610):eabd4811. doi: 10.1126/scitranslmed.abd4811. Epub 2021 Sep 8.
Weaver, BA and Cleveland, DW. (2006). Does aneuploidy cause cancer? Curr Opin Cell Biol. Dec;18(6):658-67. doi: 10.1016/j.ceb.2006.10.002. Epub 2006 Oct 12.
2018, Outstanding Teaching Award, Chang Gung University
1994-2001 Ph.D., Harvard University, Cambridge, MA
Cell and Developmental Biology
Thesis Adviser: Dr. David Pellman
1997 Protein purification course, Cold Spring Harbor Laboratory
(CSHL), Cold Spring Harbor, NY
Summer 1995 Summer student, European Molecular Biology Labs (EMBL),
Heidelberg, Germany
Project Adviser: Dr. Anthony A. Hyman
1989-1993 B.A., University of Colorado at Boulder, Boulder, CO
Honors: Magna Cum Laude in MCD Biology
Thesis Adviser: Dr. L. Andrew Staehelin
Major: Molecular, Cellular, and Developmental Biology
Major: Biochemistry
Minor: Chemistry
Job Description
To enhance anti-mitotic and senolytic anti-cancer drugs, our approach is to specifically target the Anaphase-Promoting Complex/Cyclosome (APC/C) enzyme complex to try and delay anaphase entry without inducing a mitotic cell cycle arrest (Schuyler, et al, 2018; Schuyler and Chen, 2021). We speculate, for example, that delaying anaphase entry in the presence of 10 nM paclitaxel, the clinically relevant amount, may decrease multipolar spindles in genomically stable healthy cells and increase multipolar spindle formation in genomically unstable cancer cells. Levels of multipolar spindles induced by 10 nM paclitaxel have been observed to decrease from prophase to metaphase in genomically stable CAL-51 cells, and have also been observed to decrease from metaphase into anaphase in genomically stable CAL-51, RPE-1 and MCF-10A cells, while, by contrast, in genomically unstable cells, like MDA-MB-231 and HeLa cells, the levels of multipolar spindles have been observed to increase from metaphase into anaphase (Scribano, et al., 2021). Healthy human cells have been selected to be genomically stable (Knouse, et al., 2014; Liu, et al., 2022), while cancer cells have been selected to be genomically unstable resulting in aneuploidy (Weaver and Cleveland, 2006). Thus, in the presence of 10 nM paclitaxel, a delay in anaphase entry may give genomically stable cells more time to repair their spindles, while genomically unstable cells delayed in anaphase entry may display an increase in multipolar spindles in anaphase, which will promote cancer cell death.
References:
Knouse, KA, Wu, J, Whittaker, CA, Amon, A. (2014). Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A. Sep 16;111(37):13409-14. doi: 10.1073/pnas.1415287111. Epub 2014 Sep 2.
Liu, L, Chen, H, Sun, C, Zhang, J, Wang, J, Du, M, Li, J, Di, L, Shen, J, Geng, S, Pang ,Y, Luo, Y, Wu, C, Fu, Y, Zheng, Z, Wang, J, Huang Y. (2022). Low-frequency somatic copy number alterations in normal human lymphocytes revealed by large-scale single-cell whole-genome profiling. Genome Res. Jan;32(1):44-54. doi: 10.1101/gr.275453.121. Epub 2021 Dec 28.
Schuyler, SC, Wu, YO, Chen, HY, Ding, YS, Lin, CJ, Chu, YT, Chen, TC, Liao, L, Tsai, WW, Huang, A, Wang, LI, Liao, TW, Jhuo, JH, Cheng, V. (2018). Peptide inhibitors of the anaphase promoting-complex that cause sensitivity to microtubule poison. PLoS One. Jun 8;13(6):e0198930. doi: 10.1371/journal.pone.0198930.
Schuyler, SC and Chen HY. (2021) Using budding yeast to identify molecules that block cancer cell ‘mitotic slippage’ only in the presence of mitotic poisons. Int. J. Mol. Sci. 22, 7985.
Scribano, CM, Wan, J, Esbona, K, Tucker, JB, Lasek, A, Zhou, AS, Zasadil, LM, Molini, R, Fitzgerald, J, Lager, AM, Laffin, JJ, Correia-Staudt, K, Wisinski, KB, Tevaarwerk, AJ, O'Regan, R, McGregor, SM, Fowler, AM, Chappell, RJ, Bugni, TS, Burkard, ME, Weaver, BA. (2021). Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel. Sci Transl Med. Sep 8;13(610):eabd4811. doi: 10.1126/scitranslmed.abd4811. Epub 2021 Sep 8.
Weaver, BA and Cleveland, DW. (2006). Does aneuploidy cause cancer? Curr Opin Cell Biol. Dec;18(6):658-67. doi: 10.1016/j.ceb.2006.10.002. Epub 2006 Oct 12.
Preferred Intern Educational Level
Undergraduate, Master's and PhD level candidates are welcome to apply.
Skill sets or Qualities
Students with a wide variety of backgrounds are encouraged to apply. Studied subjects may include, but are not limited to: Biology; Biochemistry; Biomedical Sciences; Chemistry; Computer Science; Data Science; Bioinformatics; Biomedical Engineering; Bioinformatics Engineering; Chemical Engineering; Artificial Intelligence; Machine Learning and Biomedical Engineering.
Job Description
To enhance anti-mitotic and senolytic anti-cancer drugs, our approach is to specifically target the Anaphase-Promoting Complex/Cyclosome (APC/C) enzyme complex to try and delay anaphase entry without inducing a mitotic cell cycle arrest (Schuyler, et al, 2018; Schuyler and Chen, 2021). We speculate, for example, that delaying anaphase entry in the presence of 10 nM paclitaxel, the clinically relevant amount, may decrease multipolar spindles in genomically stable healthy cells and increase multipolar spindle formation in genomically unstable cancer cells. Levels of multipolar spindles induced by 10 nM paclitaxel have been observed to decrease from prophase to metaphase in genomically stable CAL-51 cells, and have also been observed to decrease from metaphase into anaphase in genomically stable CAL-51, RPE-1 and MCF-10A cells, while, by contrast, in genomically unstable cells, like MDA-MB-231 and HeLa cells, the levels of multipolar spindles have been observed to increase from metaphase into anaphase (Scribano, et al., 2021). Healthy human cells have been selected to be genomically stable (Knouse, et al., 2014; Liu, et al., 2022), while cancer cells have been selected to be genomically unstable resulting in aneuploidy (Weaver and Cleveland, 2006). Thus, in the presence of 10 nM paclitaxel, a delay in anaphase entry may give genomically stable cells more time to repair their spindles, while genomically unstable cells delayed in anaphase entry may display an increase in multipolar spindles in anaphase, which will promote cancer cell death.
References:
Knouse, KA, Wu, J, Whittaker, CA, Amon, A. (2014). Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A. Sep 16;111(37):13409-14. doi: 10.1073/pnas.1415287111. Epub 2014 Sep 2.
Liu, L, Chen, H, Sun, C, Zhang, J, Wang, J, Du, M, Li, J, Di, L, Shen, J, Geng, S, Pang ,Y, Luo, Y, Wu, C, Fu, Y, Zheng, Z, Wang, J, Huang Y. (2022). Low-frequency somatic copy number alterations in normal human lymphocytes revealed by large-scale single-cell whole-genome profiling. Genome Res. Jan;32(1):44-54. doi: 10.1101/gr.275453.121. Epub 2021 Dec 28.
Schuyler, SC, Wu, YO, Chen, HY, Ding, YS, Lin, CJ, Chu, YT, Chen, TC, Liao, L, Tsai, WW, Huang, A, Wang, LI, Liao, TW, Jhuo, JH, Cheng, V. (2018). Peptide inhibitors of the anaphase promoting-complex that cause sensitivity to microtubule poison. PLoS One. Jun 8;13(6):e0198930. doi: 10.1371/journal.pone.0198930.
Schuyler, SC and Chen HY. (2021) Using budding yeast to identify molecules that block cancer cell ‘mitotic slippage’ only in the presence of mitotic poisons. Int. J. Mol. Sci. 22, 7985.
Scribano, CM, Wan, J, Esbona, K, Tucker, JB, Lasek, A, Zhou, AS, Zasadil, LM, Molini, R, Fitzgerald, J, Lager, AM, Laffin, JJ, Correia-Staudt, K, Wisinski, KB, Tevaarwerk, AJ, O'Regan, R, McGregor, SM, Fowler, AM, Chappell, RJ, Bugni, TS, Burkard, ME, Weaver, BA. (2021). Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel. Sci Transl Med. Sep 8;13(610):eabd4811. doi: 10.1126/scitranslmed.abd4811. Epub 2021 Sep 8.
Weaver, BA and Cleveland, DW. (2006). Does aneuploidy cause cancer? Curr Opin Cell Biol. Dec;18(6):658-67. doi: 10.1016/j.ceb.2006.10.002. Epub 2006 Oct 12.
Preferred Intern Educational Level
Students at the undergraduate, Master's and PhD levels are all encouraged to apply.
Skill sets or Qualities
Students with a wide variety of backgrounds are encouraged to apply. Studied subjects may include, but are not limited to: Biology; Biochemistry; Biomedical Sciences; Chemistry; Computer Science; Data Science; Bioinformatics; Biomedical Engineering; Bioinformatics Engineering; Chemical Engineering; Artificial Intelligence; Machine Learning and Biomedical Engineering.