Targeting HPV E6-Dependent Hypoxia-Induced NF-kappa B in Cervical Cancer

靶向宫颈癌中 HPV E6 依赖性缺氧诱导的 NF-κ B

• 批准号: 7927183
• 负责人: MATTHEW B RETTIG
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7927183
• 关键词: 2-oxoglutarate 3-dioxygenase proline; Accounting; Affect; Amino Acid Motifs; Amino Acids; Anus; Biochemical; CMV promoter; Cancer Etiology; Cancer Patient; Cancer cell line; Cervical; Clinical; Clinical Trials; Complex; Cues; Development; Discipline; Disease; Ectopic Expression; Enhancers; Event; Female; Gender; Gene Expression; Goals; Growth; Gynecologic Oncology; Gynecologic Pathology; HPV-High Risk; Health; Hematogenous; Human; Human Papillomavirus; Human papilloma virus infection; Hypoxia; IkappaB kinase; Infection; Injection of therapeutic agent; Link; Location; Lymphatic; Lysine; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measurement; Measures; Mediating; Medical Oncology; Metastatic Neoplasm to the Lung; Military Personnel; Mission; Mixed Function Oxygenases; Modeling; Molecular; Molecular Target; Mus; Mutagenesis; NF-kappa B; NFKB Signaling Pathway; Neoplasm Metastasis; Nude Mice; Outcome; Oxygen; Partial Pressure; Pathway interactions; Patients; Phase; Phenotype; Physicians; Pimonidazole; Play; Polyubiquitin; Polyubiquitination; Positioning Attribute; Proteins; Publishing; Radiation; Recruitment Activity; Recurrence; Regulation; Relative (related person); Research; Resistance; Response Elements; Role; Sampling; Scientist; Serotyping; Signal Pathway; Signal Transduction; Specimen; Staining method; Stains; System; TNF Receptor-Associated Factors; Tail; Therapeutic Index; Translating; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; Vaccination; Vaccines; Veins; Veterans; Vulva; Woman; Women' s Health; Work; Xenograft Model; Xenograft procedure; angiogenesis; base; cancer cell; carcinogenesis; cell type; chemotherapy; clinical phenotype; cohort; driving force; high risk; in vivo; inhibitor/antagonist; male; malignant oropharynx neoplasm; mortality; multicatalytic endopeptidase complex; penis; programs; skills; socioeconomics; tumor; tumorigenesis

DESCRIPTION (provided by applicant): PROJECT ABSTRACT Cervical cancer is the leading cause of cancer-specific mortality amongst women worldwide and the human papilloma virus (HPV) plays a pathophysiologic role in cervical carcinogenesis in over 95% of cases. For over half a century, it has become increasingly established that intratumoral hypoxia is associated with an aggressive clinical phenotype, manifested by resistance to radiation and chemotherapy, a high risk of recurrence and metastasis, and shortened overall survival. The mechanistic underpinnings that account for these adverse clinical sequelae of hypoxia have not been elucidated. We recently identified a biochemical link between HPV infection and hypoxia in cervical cancer (Cancer Cell, 14:394, 2008). Specifically, we found that the HPV-encoded E6 protein mediates prolonged activation of the NF kappa B (NF-:B) signaling pathway under hypoxic conditions. As oxygen becomes a limiting substrate, E6 effectively targets CYLD, a negative regulator of the NF-:B pathway, for proteasome-mediated degradation, and thereby allows for unrestricted NF-:B activation. Through its transcriptional activity, NF-:B drives proliferation, survival, neo-angiogenesis, invasion and metastasis. Thus, we postulate that the poor clinical outcomes associated with hypoxia can in large part be attributed to E6-mediated, hypoxia-induced NF- :B activation. In pursuit of our hypothesis, we propose three aims in which we will be: 1) elucidating some of the key remaining biochemical and molecular cues that drive the E6-CYLD interaction (Specific Aim 1), 2) examining the relative effects of hypoxia-induced versus constitutive NF-:B activation on cervical tumorigenesis and metastasis development in murine xenografts models (Specific Aim 2), and 3) prospectively studying the relationship between hypoxia and NF-:B activation and CYLD expression in tumors of cervical cancer patients (Specific Aim 3). We have assembled a team of physician-scientists with diverse skill sets from various disciplines, including medical oncology, gynecologic oncology, and gynecologic pathology to further our molecular understanding of the hypoxic phenotype. Accomplishments from this proposal represent a necessary prelude to translate our work to early phase clinical trials aimed at targeting hypoxia-induced NF-:B activation, which can take advantage of the potentially high therapeutic index afforded by HPV positivity.

描述（由申请人提供）： 项目摘要 宫颈癌是全球女性癌症特异性死亡的主要原因，人乳头瘤病毒 (HPV) 在超过 95% 的宫颈癌发生过程中发挥着病理生理作用。半个多世纪以来，人们越来越认识到肿瘤内缺氧与侵袭性临床表型相关，表现为对放疗和化疗的抵抗、复发和转移的高风险以及总生存期的缩短。造成这些缺氧不良临床后遗症的机制尚未阐明。 我们最近发现了 HPV 感染与宫颈癌缺氧之间的生化联系（Cancer Cell, 14:394, 2008）。具体来说，我们发现 HPV 编码的 E6 蛋白在缺氧条件下介导 NF kappa B (NF-:B) 信号通路的延长激活。当氧气成为限制性底物时，E6 有效地靶向 CYLD（NF-:B 途径的负调节因子），进行蛋白酶体介导的降解，从而实现不受限制的 NF-:B 激活。通过其转录活性，NF-:B 驱动增殖、存活、新血管生成、侵袭和转移。因此，我们推测与缺氧相关的不良临床结果在很大程度上可归因于 E6 介导的缺氧诱导的 NF-:B 激活。为了实现我们的假设，我们提出了三个目标：1）阐明驱动 E6-CYLD 相互作用的一些关键的生化和分子线索（具体目标 1），2）检查缺氧诱导与组成性 NF-:B 激活对小鼠异种移植模型中宫颈肿瘤发生和转移发展的相对影响（具体目标 2），以及 3）前瞻性研究宫颈癌患者肿瘤中缺氧与NF-:B激活和CYLD表达之间的关系（具体目标3）。我们组建了一支由来自不同学科（包括肿瘤内科、妇科肿瘤学和妇科病理学）的具有不同技能的医师科学家团队组成，以进一步加深我们对缺氧表型的分子理解。这项提案的成就代表了将我们的工作转化为旨在针对缺氧诱导的 NF-:B 激活的早期临床试验的必要前奏，该试验可以利用 HPV 阳性带来的潜在高治疗指数。