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

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癌症已是臺灣及日本過去41及43年的主要死因，也是全球約1/6人口的死亡原因。我們實驗室的研究目標是要增進太平洋紫杉醇的藥物效用，太平洋紫杉醇已經在二十餘種癌症的治療中取得FDA認證。MDA-MB-231細胞株中使用與臨床劑量相當的10 nM太平洋紫杉醇推論不會影響有絲分裂時的細胞週期停滯，而是會形成多極的紡錘絲(multipolar spindle)並造成兩種可能的細胞死亡途徑。第一種途徑：多極紡錘絲所造成的染色體分離失誤可導致細胞壞死、凋亡或靜止(quiescence)；第二種途徑：細胞週期後期由多極紡錘絲造成的延遲染色體(lagging chromosome)可能在細胞質分裂時形成染色質橋(chromatin bridge)並啟動cyclic GMP–AMP Synthase-Stimulator of Interferon Genes (cGAS-STING)途徑促使細胞分泌第一型干擾素(Type I interferon)召集白血球至腫瘤內透過凋亡或壞死造成免疫原性細胞死亡。亦已知太平洋紫杉醇與programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1)免疫檢查點抑制劑共同治療可以提高藥物作用。現實中許多患者無法在安全劑量的太平洋紫杉醇治療下產生反應，並產生嗜中性白血球低下症(nutropenia)、黏膜發炎(mucositis)或神經毒性等藥物副作用。我們的研究策略是在不導致細胞週期停滯的前提下針對後期轉錄因子－細胞分裂週期20酵素複合物(Anaphase-Promoting Complex/Cyclosome-Cell Division Cycle 20 (APC/C-CDC20))進行抑制以延緩細胞進入細胞週期後期，藉此提高太平洋紫杉醇的藥物作用。​​