Targeting redox control of anaplerosis as a novel metabolic cancer therapy

线粒体是小细胞器（细胞内的结构），提供能量并将各种营养物质转化为构建模块，从而使细胞发挥功能，生长和分裂。由于癌细胞通常表现出较高的生长和分裂速率，因此靶向线粒体的药物具有很高的癌症治疗潜力。然而，直到最近，用药物靶向线粒体的两个主要障碍限制了这种治疗方法。首先是缺乏有效靶向线粒体的药物：最近发现的一种名为IACS-010759的分子在靶向线粒体方面非常有效，绕过了这一障碍。第二个障碍是癌细胞改变它们使用营养物质的方式（改变代谢）的能力，以便它们能够耐受靶向线粒体的药物。我们最近报道了一种关键机制，通过这种机制，细胞改变了它们的代谢，从而绕过了靶向线粒体的药物。因此，我们建议同时靶向线粒体（使用IACS-010759）和靶向这种新的关键机制可能会提供有效的癌症治疗。我们将在实验室的细胞上测试这一想法，并在小鼠中使用饮食控制或遗传技巧来阻断允许癌细胞绕过靶向线粒体的药物的关键机制。因此，我们希望在原则上证明一种新的癌症疗法，我们将在一种特别难以治疗的癌症-三阴性乳腺癌上进行测试。

Mitochondria are small organelles (structures within cells) that provide energy and convert various nutrients into building blocks, thereby allowing cells to function, grow and divide. Because cancer cells often show elevated growth and rates of division, drugs targeting mitochondria have high potential for cancer therapy. Until recently, however, two main barriers to targeting mitochondria with drugs have limited this therapeutic approach. The first has been a lack of drugs that target the mitochondria effectively: the recent discovery of a molecule called IACS-010759 that is highly effective at targeting mitochondria has circumvented this barrier. The second barrier has been the ability of cancer cells to change the way that they use nutrients (altered metabolism) so that they can tolerate drugs targeting mitochondria. We recently reported a critical mechanism through which cells change their metabolism to bypass drugs targeting mitochondria. We therefore propose that targeting mitochondria (with IACS-010759) and targeting this new critical mechanism simultaneously may provide an effective cancer therapy. We will test this idea upon cells in the laboratory and also using dietary control or genetic tricks in mice to block the critical mechanism that allows cancer cells to bypass agents targeting mitochondria. We thereby hope to demonstrate, in principle, a new cancer therapy and we will test it upon a particularly hard-to-treat cancer - triple negative breast cancer.