Research Project: 以異位型ATP合成酶抑制劑為基礎之抗肺癌合併治療：應用系統生物學至網路醫學
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摘要：ATP合成酶是一種蛋白質複合體，催化生物體能量來源ATP的合成。長期以來，動物ATP合成酶都被認為只存在於粒線體，然而，近年研究卻發現在某些種類的細胞，包括癌細胞，其細胞表面也能發現ATP合成酶，此種合成酶因而被被稱作胞外ATP合成酶。我們在先前研究中已發現ATP合成酶抑制劑可藉由抑制胞外ATP合成酶打擊肺癌細胞的生長，且不影響正常的粒線體功能。另一方面，「體學」的技術已在過去十年中對抗癌新藥的發展做出極大的貢獻，並將癌症治療從傳統化療提升到以個人藥物為策略的境界。然而，因腫瘤細胞內的基因異質化、蛋白間交互作用、及後轉議修飾的不同調控所造成的抗藥性及副作用，往往限制了分子藥物標靶的可利用性。為了提升ATP合成酶抑制劑在肺炎治療的效果，本計畫目的為從蛋白質交互作用陣列分析，及磷酸化蛋白體資料分析中，找到有潛力的藥物標靶分子，作為增進ATP合成酶抑制劑治療效果的合併藥物。我們將從非生物及生物兩種模式監測此合併藥物對腫瘤發展的生理影響，並以此評估合併藥物在肺癌的療效。<br> Abstract: ATP synthase is a multimeric protein complex that catalyzes the synthesis of ATP. For a long time, animal ATP synthase was believed to be found only in mitochondria; however, in recent studies, ATP synthase was also found on the extracellular surface of some cell types including cancer cells, named as ectopic ATP synthase. Our previous studies have shown that ATP synthase inhibitor is a potential drug candidate for fighting lung cancer by blocking the ectopic ATP synthase without obvious damages to mitochondrial function. Over the past decades, the “omic” technologies have contributed to the discovery of new novel targets for tumor pathogenicity, leading the cancer therapy from conventional one-size-fits-all chemotherapy to the personalized medicine strategy. However, the resistance and side effects resulted from the intratumor genetic heterogeneity, and the regulation variability at protein-protein interactions and post-translational level always limit the utility of molecule targeted drugs. To improve the therapeutic efficiency of ATP synthase inhibitor in lung cancer, we plan to combine ATP synthase inhibitor with other drug candidates arisen from protein interaction array or protein phosphorylation profiles. The influences of the combinatorial therapies on tumor progression will be evaluated by monitoring the physiological effects of different combinatorial treatments in vitro and in vivo.
Keywords
胞外ATP合成酶
肺癌
合併治療
ecto-ATP synthase
lung cancer
combinatorial therapy
肺癌
合併治療
ecto-ATP synthase
lung cancer
combinatorial therapy