Changing the mechanism of cancer therapeutics

抗癌药物通常通过诱导细胞凋亡来发挥作用。不幸的是，大量证据表明 细胞凋亡可能不是杀死癌细胞的好方法--例如，细胞凋亡导致caspase依赖的快速 耐药细胞的肿瘤再繁殖是因为凋亡细胞向 未被杀死的邻近细胞和凋亡会导致非免疫原性肿瘤细胞杀伤，从而减少 产生有效的抗肿瘤免疫反应的可能性。我们实验室最近的研究表明， 可以调节和改变细胞凋亡刺激的作用模式，而不是通过 细胞凋亡，细胞死于坏死性下垂。坏死性下垂是一种程序性坏死，不涉及 与细胞凋亡相比，它具有更强的免疫原性，因此可能是一种更好的杀死癌细胞的方法。在……里面 这项试点拨款我们将检验中心假设，即有可能操纵正常的细胞过程， 自噬，以改变抗癌药物的作用方式，使其通过 坏死性上睑下垂代替或同时出现细胞凋亡。这项工作建立在我们小组之前的研究基础上，并 旨在开发试点数据，以确定我们提议的方法的可行性。 如果我们确定了我们的中心假设的可行性，我们就应该有了开发更大项目的基础 来测试是否有可能和值得尝试操纵不仅我们是否杀死癌细胞，而且 控制我们如何杀死他们。为了实现这些目标，我们有两个目标。目标1.测试自噬机器是否 调节人类癌细胞的坏死性下垂。目的2.检测人的坏死性下垂能力是否重新激活 具有RIPK3沉默的肿瘤细胞允许将自噬调节扩大到更多的癌症 细胞。在完成这一小笔试点拨款后，我们将准备开发一个更大的项目，以测试我们是否可以 改变目前癌症治疗的范式以控制肿瘤细胞死亡的机制作为一种方式 提高癌症治疗水平。

Anti-cancer drugs usually work by inducing apoptosis. Unfortunately a significant body of evidence suggests that apoptosis may not be a good way to kill cancer cells– e.g. apoptosis causes rapid, caspase-dependent tumor repopulation of drug-resistant cells because apoptotic cells send growth promoting signals to neighboring cells that aren't killed and apoptosis causes non-immunogenic tumor cell killing thus reducing the likelihood of generating an effective anti-tumor immune response. Recent work from our lab suggests that it is feasible to regulate and change the mode of action of an apoptotic stimulus so that instead of killing by apoptosis, the cell dies by necroptosis. Necroptosis is a form of programmed necrosis, which does not involve caspases and is more immunogenic than apoptosis that may, therefore, be a better way to kill cancer cells. In this pilot grant we will test the central hypothesis that it is possible to manipulate a normal cell process, autophagy, in order to change the mode of action of anti-cancer drugs so that they kill human tumor cells by necroptosis instead of or as well as apoptosis. This work builds on previous studies from our group and is intended to develop pilot data establishing feasibility of our proposed approach. If we establish the feasibility of our central hypothesis, we should have a foundation to develop a larger project to test if it is possible and worthwhile to try to manipulate not only whether or not we kill cancer cells but also control how we kill them. To achieve these goals we have two aims. Aim 1. Test if the autophagy machinery regulates necroptosis in human cancer cells. Aim 2. Test if re-activation of necroptosis capacity in human tumor cells with RIPK3 silencing allows broadening of the autophagy regulation of necroptosis to more cancer cells. Upon completing this small pilot grant, we will be positioned to develop a larger project to test if we can change the current paradigm of cancer therapy to control the mechanism of tumor cell death as a way to improve cancer therapy.