Changing the mechanism of cancer therapeutics

改变癌症治疗机制

• 批准号: 9752501
• 负责人: Andrew M Thorburn
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752501
• 关键词: Address; Antineoplastic Agents; Apoptosis; Apoptotic; Autophagocytosis; Autophagosome; Biological; Caspase; Cell Death; Cell physiology; Cells; Cessation of life; Characteristics; Clinic; Complex; Cyclic AMP-Dependent Protein Kinases; Cytotoxic Chemotherapy; Data; Defect; Drug resistance; Foundations; Goals; Grant; Growth; Human; Immune system; Koreans; Lead; Malignant Neoplasms; Methods; Mus; Necrosis; Normal Cell; Normal tissue morphology; Outer Mitochondrial Membrane; Patients; Pharmaceutical Preparations; Pilot Projects; Population; Positioning Attribute; Prostate; RIPK1 gene; RIPK3 gene; Regulation; Reporting; Research Project Grants; Resistance; Role; Signal Transduction; Stimulus; TNFSF10 gene; Testing; Therapeutic; Therapeutic Index; Toxic effect; Tumor Immunity; Tumor Suppressor Genes; Work; anti-tumor immune response; cancer cell; cancer therapy; cell injury; cell killing; chemotherapy; design; immunogenic cell death; improved; inhibition of autophagy; neoplastic cell; novel strategies; patient response; programs; rapid growth; recruit; response; scaffold; side effect; tumor

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.

抗癌药物通常通过诱导的凋亡作用。不幸的是，大量证据表明 这种凋亡可能不是杀死癌细胞的好方法 - 例如凋亡导致快速，caspase依赖性 肿瘤对药物耐药细胞的重生，因为凋亡细胞将促进信号的生长促进信号发送到 未杀死和凋亡的相邻细胞会导致非免疫原性肿瘤细胞杀死，从而减少 产生有效的抗肿瘤免疫反应的可能性。我们实验室的最新工作表明这是 可行的调节和改变凋亡刺激的作用方式，以免杀死 细胞凋亡，细胞因坏死病而死亡。坏死性是编程坏死的一种形式，不涉及 胱天蛋白酶酶比细胞凋亡更为免疫原性，因此，凋亡可能是杀死癌细胞的更好方法。在 该试点赠款我们将测试中心假设，即有可能操纵正常的细胞过程， 自噬，为了改变抗癌药物的作用方式，以便通过 坏死性而不是或凋亡。这项工作以我们小组以前的研究为基础，是 旨在制定试点数据，以确定我们提出的方法的可行性。 如果我们确定中心假设的可行性，我们应该有一个基础来开发一个更大的项目 测试是否有可能，值得尝试操纵我们是否杀死癌细胞，还可以操纵 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。测试自噬机械是否 调节人类癌细胞中坏死性。 AIM 2。测试人类坏死能力是否重新激活 用RIPK3沉默的肿瘤细胞允许扩大坏死性的自噬调节对更多的癌症 细胞。完成这项小型飞行员赠款后，我们将有权开发一个更大的项目，以测试是否可以 改变当前的癌症治疗范式，以控制肿瘤细胞死亡的机制 改善癌症疗法。