Novel targeted therapies for HPV-associated Non-AIDS-defining cancers (Biospecimens/Biocohort)

针对 HPV 相关非艾滋病定义癌症的新型靶向疗法（生物样本/生物队列）

• 批准号: 10620083
• 负责人: STEVEN Terry ROSEN
• 金额: $ 25万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620083
• 关键词: AIDS related cancer; Blood; COVID-19 vaccine; Cell Death; Cell Line; Data; Dependence; Development; Engineering; Etiology; Gene Delivery; Gene-Modified; Genome; Genomics; Goals; Grant; Growth; HIV; HPV-High Risk; Head Cancer; Head and Neck Cancer; Head and neck structure; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papillomavirus 16; Individual; Infection; Intervention; Maintenance; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Methods; Mission; Modeling; Neck; Oncogenes; Oncogenic Viruses; Oncornaviruses; Patient Representative; Persons; Promoter Regions; Proteins; Public Health; RNA delivery; Repressor Proteins; Research; System; Testing; Therapeutic; Therapeutic Intervention; United States National Institutes of Health; Viral; Viral Genes; Viral Oncogene; Vulnerable Populations; Work; Zinc Fingers; anti-cancer; carcinogenicity; co-infection; combat; high risk; human papilloma virus oncogene; in vivo; in vivo Model; innovation; leukemia; lipid nanoparticle; mouse model; nanoparticle delivery; new therapeutic target; novel; novel therapeutic intervention; oncogene addiction; patient derived xenograft model; success; targeted treatment; therapeutic RNA; therapeutic development; therapeutic gene; therapeutic target; tumor

Project Summary/Abstract Novel targeted therapies for HPV-associated Non-AIDS-defining cancers (Biospecimens/Biocohort) The incidents of non-AIDS-defining cancers (NADC) are increasing in HIV-infected individuals (HIVIIs), urging the development of therapeutic interventions. Many HIV-associated cancers are a result of co-infections with oncogenic viruses, and the high-risk human papillomavirus (HPV) is prevalent in the development of several NADCs, including head-and-neck (HNC) and anal cancers. Importantly, the HPV viral oncogenes are involved in the transformation and maintenance of these cancers and are considered unique targets in HPV-associated malignancies. Often considered `undruggable', these viral genes are susceptible to targeted gene therapeutic strategies and we have developed a novel, potent zinc finger protein (ZFP) that can strongly repress viral oncogenes to elicit anti-cancer effects; a promising approach to HPV-associated NADCs. Furthermore, lipid nanoparticles (LNPs) are a therapeutically relevant non-viral delivery system, which we have used previously for in vivo delivery of RNA-based therapeutics. Importantly, even though the HPV oncogenes represent viable therapeutic targets, there are no studies investigating the potential anti-proliferative effect of targeting the viral oncogenes in HPV-associated tumors from HIVIIs in vivo. Our long-term goal is to develop innovative interventions for the treatment of virally driven cancers emerging in HIVIIs, with the objective of this project to use LNP-delivered ZFP repressors to inactive HPV oncogenes in NADCs. Guided by our strong preliminary data and expertise using targeted repressors and nanoparticle delivery systems, we propose two complementary but distinct objectives, 1) the characterization of novel, potent ZFP repressors for anti-proliferative effects in HPV- associated cell line models relevant to NADCs, and 2) to assess LNP-delivered anti-HPV effectors to inhibit HPV-associated HNCs from HIVIIs in a patient-derived xenograft (PDX) murine model. Collectively, this work will be impactful by developing an innovative targeted repressor to inhibit HPV-associated NADCs, offering a novel intervention to malignancies increasing in HIVIIs.

项目摘要/摘要 针对HPV相关的非艾滋病定义癌症的新靶向疗法(生物制剂/生物队列) 艾滋病毒感染者(HIVII)中非艾滋病定义癌症(NADC)的发病率正在增加，敦促 治疗干预措施的发展。许多与艾滋病毒相关的癌症是由与 致癌病毒和高危人乳头瘤病毒(HPV)是几种流行的发展 NADC，包括头颈部(HNC)和肛门癌。重要的是，hpv病毒致癌基因与 在这些癌症的转化和维持中，并被认为是HPV相关的独特靶点 恶性肿瘤。这些病毒基因通常被认为是“无法用药的”，因此很容易受到靶向基因治疗的影响 我们已经开发出一种新型的、有效的锌指蛋白(ZFP)，它可以强烈地抑制病毒 癌基因诱导抗癌作用；HPV相关NADCs的一种有前途的方法。此外，脂类 纳米粒(LNPs)是一种与治疗相关的非病毒传递系统，我们以前曾将其用于 以RNA为基础的治疗药物的体内传递。重要的是，尽管人乳头瘤病毒癌基因是可行的 治疗靶点，目前还没有研究探讨靶向病毒的潜在抗增殖作用。 HIVIIs体内HPV相关肿瘤的癌基因。我们的长远目标是发展创新 对艾滋病毒感染者中出现的病毒驱动的癌症的干预措施，该项目的目标是 使用LNP递送的ZFP抑制物来灭活NADCs中的HPV癌基因。在我们强劲的初步数据的指导下 和使用靶向阻遏物和纳米颗粒传递系统的专业知识，我们提出了两个互补的但 明确的目标，1)表征新的，有效的ZFP抑制物在HPV中的抗增殖作用- 与NADCs相关的相关细胞系模型，以及2)评估LNP递送的抗HPV效应物抑制 在患者来源的异种移植(PDX)小鼠模型中来自HIVII的HPV相关HNC。总体而言，这项工作 将通过开发一种创新的靶向抑制物来抑制HPV相关的NADCs，从而产生影响，提供 针对HIV感染者不断增加的恶性肿瘤的新干预措施。