Rewiring of epigenetic DNA damage response pathways in HPV-induced cancer

项目摘要/摘要 感染人乳头瘤病毒(HPV)导致颈部、头部和 颈部和肛门癌。放射治疗是这些肿瘤治疗的基石。然而， 由于复发率高，局部晚期疾病患者的临床结果仍然很差 费率。因此，迫切需要提高放射治疗对这些肿瘤的疗效。表观遗传 信号通路在提供合适的临床靶点的DNA损伤反应中起着至关重要的作用 以提高放射治疗的疗效。我们证明了HPV蛋白的表达 E6和E7改变癌细胞的表观遗传信号。我们假设这些表观基因组 改变导致肿瘤依赖于替代的表观遗传途径来应对DNA 损坏。使用CRISPR/Cas9筛查，我们发现HPV阳性的癌细胞选择性地 依赖染色质修饰物NSL1和E3泛素连接酶RNF168才能存活下来。 这项建议的目的是确定dna损伤反应(Ddr)的机制。 在HPV诱导的表观遗传学改变的背景下，受这些途径的调控。我们的工作将 利用HPV诱导的表观基因组建立肿瘤靶向治疗的新概念 在保留健康组织的同时，允许特定靶向癌细胞的改变。这项工作 在这里提出的将在丹尼斯·哈拉汉博士的指导下进行，他是临床的领导者 和实验性放射肿瘤学。应聘者为医学博士/博士学位，受过临床培训 寻求基础研究方面的进一步培训的放射肿瘤学专家。他的长期目标是建立 一个独立的研究实验室，研究表观遗传学在DDR中的作用。预计 该项目将对复员方案和放射肿瘤学以及 为候选人成为一名独立调查员做好准备。

Project summary/abstract Infection with human papilloma virus (HPV) causes endemic occurrence of cervical, head and neck and anal cancers. Radiotherapy is the cornerstone treatment for these tumors. However, clinical outcomes in patients with locally advanced disease remain poor due to high recurrence rates. Thus, there is a critical need to improve the efficacy of radiation in these tumors. Epigenetic signaling pathways play a crucial role in DNA damage response providing suitable clinical targets for improving the efficacy of radiotherapy. We demonstrate that expression of the HPV proteins E6 and E7 alters epigenetic signaling in cancer cells. We hypothesize that these epigenomic alterations cause tumor dependence on alternative epigenetic pathways to cope with DNA damage. Using a CRISPR/Cas9 screen we discovered that HPV-positive cancer cells selectively depend on the chromatin modifier NSL1 and the E3 ubiquitin ligase RNF168 to survive radiation. The goal of this proposal is to determine the mechanisms of DNA damage response (DDR) regulated by these pathways in the setting of HPV-induced epigenetic changes. Our work will establish a novel concept of tumor-targeted therapy by harnessing HPV-induced epigenomic alterations to allow specific targeting of cancer cells while sparing healthy tissues. The work proposed here will be conducted under the mentorship of Dr. Dennis Hallahan, a leader clinical and experimental radiation oncology. The candidate is an MD/PhD with training in clinical radiation oncology who seeks further training in basic research. His long-term goal is to establish an independent research laboratory studying the role of epigenetics in DDR. It is anticipated that the project will result in impactful contributions to the fields of DDR and Radiation Oncology and prepare the candidate for a career as an independent investigator.