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: 8413407
• 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/8413407
• 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）： 宫颈癌是世界范围内女性癌症特异性死亡的主要原因，而人乳头瘤病毒（HPV）在95%以上的病例中的宫颈癌发生中起着病理生理作用。半个多世纪以来，越来越多的人认为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缩短。解释缺氧这些不良临床后遗症的机制基础尚未阐明。 我们最近鉴定了宫颈癌中HPV感染和缺氧之间的生物化学联系（Cancer Cell，14：394，2008）。具体地说，我们发现HPV编码的E6蛋白介导了缺氧条件下NF-κ B（NF-：B）信号通路的长期激活。当氧成为限制性底物时，E6有效地靶向CYLD（NF-：B途径的负调节剂）用于蛋白酶体介导的降解，从而允许不受限制的NF-：B活化。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，我们推测缺氧相关的不良临床结果在很大程度上归因于E6介导的缺氧诱导的NF-：B激活。在追求我们的假设，我们提出了三个目标，我们将：1）阐明一些关键的剩余生化和分子线索，驱动E6-CYLD相互作用（具体目的1），2）在小鼠异种移植物模型中检查缺氧诱导的与组成性NF-：B活化对宫颈肿瘤发生和转移发展的相对作用（具体目的2），和3）前瞻性研究缺氧和NF-：宫颈癌患者肿瘤中的B活化和CYLD表达（具体目标3）。我们已经组建了一个由来自不同学科（包括医学肿瘤学、妇科肿瘤学和妇科病理学）的具有不同技能的医生-科学家组成的团队，以进一步加深我们对缺氧表型的分子理解。该提案的成就代表了将我们的工作转化为旨在靶向低氧诱导的NF-：B活化的早期临床试验的必要前奏，该试验可以利用HPV阳性提供的潜在高治疗指数。