Strategies to Disrupt Oncogenic Transcription in RCC Tumors

·项目概要· 肾细胞癌（RCC）是美国第8种最常见的成人癌症。尽管最近有所改善， 在治疗选择中，大多数转移性RCC患者继续死于这种疾病， 导致全球每年超过10万人死亡因此，重要的是要确定新的治疗策略， 有效治疗这种致命疾病。我们的初步研究表明，雅普/TAZ功能的主调节器 在大多数RCC亚型的核心致癌转录网络中， RCC肿瘤的转录和代谢稳态。我们建议的第一个主要目的是确定 首个雅普/TAZ抑制剂在患者源性RCC中的治疗效果和作用机制 肿瘤模型除了体内疗效研究，我们将采用尖端的表观基因组技术，包括 Cut&Tag、omni-ATAC-seq和3 '-RNAseq，以探测雅普/TAZ的遗传和药理学抑制 影响雅普/TAZ转录复合物的组成和活性，以及全局表观遗传和 在RCC肿瘤中的转录景观。通过这些分析，我们将能够获得关键的见解， 雅普/TAZ在RCC肿瘤中的分子功能，而且还重建了RCC的核心整体 致癌转录网络这项建议的第二个主要目的是发展机制驱动 联合策略，以更有效地治疗RCC肿瘤。通过高通量药物筛选， 通过广泛的机制研究，我们最近将MEK和BET抑制剂确定为两大类药物， 与雅普/TAZ遗传或药理学抑制作用强烈协同作用，以抑制致癌转录 并在体外和体内清除雅普/TAZ成瘾的肿瘤细胞。根据这些结果，我们将调查 低剂量的MEK或BET抑制剂与雅普/TAZ抑制剂组合是否可导致持久的肿瘤 在RCC PDX模型中回归而不增加系统毒性。此外，我们还将开展功能性 基因组研究，以阐明MEK和BET抑制剂如何充分发挥雅普/TAZ失活的作用，导致 RCC致癌转录网络的崩溃。最后，我们将研究雅普/TAZ抑制剂 影响RCC肿瘤分泌物组和免疫浸润以及是否可用于克服耐药 免疫检查点抑制剂总之，这些研究将大大提高我们对串扰的理解 以及控制RCC细胞生长和存活的致癌途径之间的冗余， 从而产生更有效的组合策略以克服RCC患者的治疗抗性。

• 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.