Novel Treatment Strategies for Cancer

项目总结：癌症的新治疗策略 尽管进行了数十年的临床试验，但非透明细胞肾细胞癌（NCCRCC）的总生存率一直很低，这突出了开发有效治疗方法的迫切需要。这是因为与传统的透明细胞肾细胞癌相比，NCRCC没有生物学上合理的治疗方法。因此，NCRCC缺乏治疗是一个关键的临床未满足的需求。 我们通过开发一种新的JAK和AKT抑制剂组合治疗来解决这一需求，该治疗可以在体外和小鼠模型中阻断NCCRCC癌细胞的生长。重要的是，我们发现了JAK-AKT抑制治疗后的非基因组早期适应性生存信号，其特征在于“脂质重编程”转录状态。这种非基因组代谢适应导致磷脂水解以动员溶血磷脂和游离脂肪酸来维持脂肪酸氧化和氧化磷酸化。我们的目标是明确建立这种观察到的效果的机制和功能基础。这使我们假设，诱导代谢灾难是必不可少的诱导细胞毒性。我们将测试这一假设如下：在目标1中，我们将探讨如何线粒体生物发生和动力学收敛，以增加呼吸代谢应激的设置。接下来，在目标2中，我们将阐明溶血磷脂和脂肪酸如何在营养耗尽的情况下维持癌细胞存活。重要的是，在这两个目标中，我们将寻求发现可能导致更有效的治疗组合的分子靶点。 将这项研究扩展到更广泛的科学和临床社区将具有重要意义，因为这项工作将建立共同靶向信号传导和代谢途径的框架，以改善和延长NCCRCC患者的生命。

PROJECT SUMMARY: Novel treatment strategies for cancer The urgent need to develop effective treatments for non-clear cell renal cell carcinomas (NCCRCC) is underscored by consistently poor overall survival, despite decades of clinical trials. This is because there are no biologically rational treatments for NCCRCC, compared to conventional clear cell renal cell carcinomas. Accordingly, the lack of therapies for NCCRCC is a critical clinical unmet need. We addressed this need by developing a novel JAK and AKT inhibitor combination treatment that blocked the growth of NCCRCC cancer cells invitro and in mouse models. Importantly, we discovered a non-genomic early adaptive survival signal following JAK-AKT inhibition therapy characterized by a “lipid reprogrammed” transcriptional state. This non-genomic metabolic adaptation resulted in phospholipid hydrolysis to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Our objective is to definitely establish the mechanistic and functional basis for this observed effect. This leads us to hypothesize that the induction of metabolic catastrophe is essential to inducing cytotoxicity. We will test this hypothesis as follows: In Aim 1, we will explore how mitochondrial biogenesis and dynamics converge to increase respiration in the setting of metabolic stress. Next, in Aim 2, we will elucidate how lysophospholipids and fatty acids are marshalled to maintain cancer cell survival despite nutrient depletion. Importantly, in both aims we will seek to discover molecular targets that can potentially lead to even more potent therapeutic combinations. The extension of this research to the broader scientific and clinical community will be significant because this work will establish the framework for co-targeting of signaling and metabolic pathways to improve and extend the lives of patients with NCCRCC.