Strategies to Disrupt Oncogenic Transcription in RCC Tumors

·项目总结· 肾细胞癌是美国第八种最常见的成人癌症。尽管最近有所改善 在治疗方案上，大多数转移性肾细胞癌患者继续死于这种疾病，结果 全球每年有超过10万人死亡。因此，重要的是确定新的治疗策略以获得更多 有效地治疗这种致命的疾病。我们的初步研究表明，YAP/TAZ发挥着主要的调节作用 在大多数肾癌亚型中的核心致癌转录网络，是维持 肾癌肿瘤的转录和代谢动态平衡。我们建议的第一个主要目标是确定 一类YAP/TAZ抑制剂治疗肾癌的疗效及作用机制 肿瘤模型。除了体内药效研究外，我们还将使用尖端的表观基因组学技术，包括 Cut&Tag、omni-ATAC-seq和3‘-RNAseq研究YAP/TAZ的遗传和药理抑制 影响YAP/TAZ转录复合体的组成和活性以及全球表观遗传和 肾细胞癌肿瘤中的转录图谱。通过这些分析，我们将能够获得对 YAP/TAZ在肾癌中的分子功能，但也重建了肾癌的核心集合 致癌转录网络。这项建议的第二个主要目标是发展机制驱动 联合策略，以更有效地治疗肾癌肿瘤。通过高通量药物筛选和 广泛的机制研究，我们最近确定了MEK和BET抑制剂作为两类主要的药物 强协同YAP/TAZ的遗传或药物抑制作用抑制癌基因转录 并在体内外清除YAP/TAZ成瘾的肿瘤细胞。根据这些结果，我们将调查 小剂量的MEK或BET抑制剂与YAP/TAZ抑制剂联合使用是否会导致持久的肿瘤 肾癌PDX模型中不增加系统毒性的回归。此外，我们还将进行功能 基因组研究阐明MEK和BET抑制剂如何充分发挥YAP/TAZ失活的作用，导致 肾细胞癌致癌转录网络的崩溃。最后，我们将研究YAP/TAZ抑制剂是如何 影响肾细胞癌肿瘤分泌体和免疫浸润物及其是否可用于克服耐药性 免疫检查点抑制剂。总之，这些研究将大大提高我们对相声的理解。 以及控制肾细胞癌细胞生长和存活的致癌途径之间的冗余，潜在地 产生更有效的联合策略来克服肾癌患者的治疗耐药性。

• PROJECT SUMMARY • Renal cell carcinoma (RCC) is the 8th most common form of adult cancer in the US. Despite recent improvement in treatment options, the majority of patients with metastatic RCC continue to succumb to this disease, resulting in over 100,000 deaths per year worldwide. Thus, it is important to identify novel therapeutic strategies to more effectively treat this deadly disease. Our preliminary studies suggest that YAP/TAZ function as master regulators of the core oncogenic transcriptional network across most subtypes of RCC and are required for maintaining the transcriptional and metabolic homeostasis of RCC tumors. The first major aim of our proposal is to determine the therapeutic efficacies and mechanisms of action of first-in-class YAP/TAZ inhibitors in patient-derived RCC tumor models. Besides in vivo efficacy studies, we will employ cutting-edge epigenomic techniques including Cut&Tag, omni-ATAC-seq and 3’-RNAseq to probe how genetic and pharmacological inhibition of YAP/TAZ affect the compositions and activities of the YAP/TAZ transcriptional complexes and the global epigenetic and transcriptional landscape in RCC tumors. Through these analyses, we will be able to gain critical insights into the molecular functions of YAP/TAZ in RCC tumors, but also reconstruct the core ensemble of the RCC oncogenic transcriptional network. The second major aim of this proposal is to develop mechanism-driven combination strategies to more effectively treat RCC tumors. Through high-throughput drug screening and extensive mechanistic studies, we recently identified MEK and BET inhibitors as two major classes of drugs that strongly synergize with genetic or pharmacological inhibition of YAP/TAZ to suppress oncogenic transcription and eliminate YAP/TAZ-addicted tumor cells in vitro and in vivo. Based on these results, we will investigate whether combining low doses of MEK or BET inhibitors with YAP/TAZ inhibitors could lead to durable tumor regression without increasing systematic toxicities in RCC PDX models. Furthermore, we will conduct functional genomic studies to elucidate how MEK and BET inhibitors amply the effects of YAP/TAZ inactivation, leading to the collapse of the RCC oncogenic transcriptional network. Finally, we will investigate how YAP/TAZ inhibitors affect the RCC tumor secretome and immune infiltrates and whether they could be used to overcome resistance to immune checkpoint inhibitors. Together, these studies will greatly enhance our understanding of the crosstalk and redundancies between the oncogenic pathways that govern the growth and survival of RCC cells, potentially yielding more effective combination strategies to overcome treatment resistance in RCC patients.