LXRα induced lipotoxicity for cancer treatment

实体瘤由于其特定的生物合成需求和特定的微环境，在发育过程中代谢途径发生了显着的变化。然而，基于抑制生物合成途径的癌症治疗的发展往往受到代谢网络的高度可塑性和适应性的限制，例如导致代偿途径的激活或癌细胞与肿瘤环境之间代谢产物的增加。在DFG研究小组FOR2314中，我们最近可以证明，由肝X受体α(LxRα)的药理激活所触发的促进脂肪生成是治疗肝癌的一种新的治疗策略。LXRα介导的脂肪酸合成和伴随的Raf抑制相结合导致氧化应激，诱导关键的内质网应激反应，并随后导致不同的小鼠和人肝癌细胞的凋亡。我们的机制研究证实Raf-1是肝脏肿瘤中脂代谢的重要调节因子。我们发现Raf-1与硬脂酰辅酶A脱饱和酶-1(SCD1)直接相互作用，SCD1是将饱和脂肪酸转化为单不饱和脂肪酸的中心酶，从而维持了肝癌细胞中SCD1蛋白的稳定性。DFG-OUT Raf抑制剂对Raf-1的抑制降低了SCD1蛋白的丰度，导致在持续脂肪生成下癌细胞中饱和脂肪酸的有毒积累和代谢应激。对基因定义或脂肪性肝炎(NASH)诱导的小鼠肝癌模型和人肝癌异种移植模型的治疗研究表明，由LXR激动剂和DFG-out Raf抑制剂组成的联合治疗有效地抑制了肝癌的发展，并延长了荷瘤动物的生存时间。这种疗法在小鼠中耐受性良好，甚至对已经患有脂肪肝的动物也是如此。通过这项提议，我们的目标是进一步研究我们的脂毒疗法和已鉴定的Raf-1-SCD1蛋白复合体。我们想了解Raf-1是如何与SCD1相互作用的，以及这种相互作用是如何维持SCD1蛋白的稳定性的。此外，我们想要确定这种蛋白质复合体在其他肿瘤实体中的相关性，并评估这些肿瘤对这种脂毒疗法的治疗反应。为了进一步提高这种脂毒疗法的治疗效果，我们的目标是确定长期治疗后产生治疗抵抗的机制。我们将进行mRNA表达分析和体内RNA干扰筛选，以确定潜在的抗性机制。最后，我们计划探索免疫系统在这种脂毒疗法治疗肿瘤中的作用。我们将分析免疫细胞在治疗过程中的招募情况，并确定它们在免疫缺陷小鼠治疗反应中的作用。

Solid tumors acquire significant changes in metabolic pathways during development due to their specific biosynthetic demands and their particular microenvironment. However, the development of cancer therapies that are based on the inhibition of biosynthetic pathways is often limited by the high plasticity and adaptability of metabolic networks, e.g. resulting in activation of compensatory pathways or in an increased exchange of metabolites between cancer cells and the tumor environment. Therefore, such therapies could not be translated into efficient clinical applications so far.Within the DFG research group FOR2314, we could recently show that enhanced liponeogenesis, triggered by a pharmacological activation of the Liver X receptor alpha (LXRα), represents a new therapeutic strategy for the treatment of liver carcinoma (HCC). A combination of LXRα mediated fatty acid synthesis and concomitant Raf suppression results in oxidative stress, induction of a critical endoplasmic reticulum stress response and subsequently in apoptosis of different murine and human liver cancer cells. Our mechanistic studies identified Raf-1 as an important regulator of lipid metabolism in liver tumors. We found that Raf-1 directly interacts with Stearoyl-CoA desaturase-1 (SCD1), the central enzyme for the conversion of saturated into mono-unsaturated fatty acids and thereby maintains SCD1 protein stability in HCC cells. Inhibition of Raf-1 by DFG-out Raf inhibitors diminished SCD1 protein abundance, leading to toxic accumulation of saturated fatty acids and metabolic stress in cancer cells under sustained lipogenesis. Treatment studies in genetically defined or steatohepatitis (NASH)-induced liver cancer mouse models and xenograft models of human HCC revealed that a combinatorial therapy, comprising an LXR agonist and a DFG-out Raf inhibitor efficiently suppress liver cancer development and prolong the survival of tumor bearing animals. Such a therapy was well tolerated by mice, even by animals that already suffer from a fatty liver disease.With this proposal, we aim to further investigate our lipotoxic therapy and the identified Raf-1-SCD1 protein complex. We want to understand how Raf-1 interacts with SCD1 and how this interaction maintains SCD1 protein stability. Furthermore, we want to determine the relevance of this protein complex in other tumor entities and evaluate the therapeutic response of these tumors to this lipotoxic therapy. To further improve the therapeutic effect of this lipotoxic therapy, we aim to identify mechanisms of therapy resistance upon long-term treatment. We will perform mRNA expression analyses and an in vivo RNA interference screen to identify potential resistance mechanisms. Finally, we plan to explore the role of the immune system in tumors treated with this lipotoxic therapy. We will analyse the recruitment of immune cells during treatment and determine their role in the treatment response with immunodeficient mice.