Scott C. Schuyler(曲桐)

Targeting APC/C-CDC20 to Enhance the Effectiveness of Paclitaxel

Cancers have been the leading cause of death in Taiwan and Japan for the past 41 and 43 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.  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 to try and delay anaphase entry without inducing a mitotic cell cycle arrest which may enhance the effectiveness of paclitaxel