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）

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要针对 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） HIV 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同时感染艾滋病毒的结果致癌病毒，高危人乳头瘤病毒 (HPV) 在多种疾病的发展中普遍存在 NADC，包括头颈癌 (HNC) 和肛门癌。重要的是，HPV 病毒癌基因也参与其中在这些癌症的转化和维持中，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“不可成药的”，很容易受到靶向基因治疗的影响我们开发了一种新型有效的锌指蛋白（ZFP），可以强烈抑制病毒致癌基因引发抗癌作用； HPV 相关 NADC 的一种有前途的方法。此外，脂质纳米颗粒（LNP）是一种治疗相关的非病毒传递系统，我们之前曾将其用于基于 RNA 的治疗药物的体内递送。重要的是，尽管 HPV 癌基因代表着可行的治疗靶点，目前还没有研究调查针对病毒的潜在抗增殖作用体内 HIVII 的 HPV 相关肿瘤中的癌基因。我们的长期目标是开发创新治疗艾滋病病毒感染者中出现的病毒驱动癌症的干预措施，该项目的目标是使用 LNP 传递的 ZFP 阻遏物来抑制 NADC 中失活的 HPV 癌基因。以我们强大的初步数据为指导和使用靶向阻遏物和纳米粒子递送系统的专业知识，我们提出了两种互补但不同的目标，1) 新型、有效的 ZFP 阻遏物的表征，用于 HPV- 的抗增殖作用与 NADC 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。总的来说，这部作品将通过开发一种创新的靶向阻遏物来抑制 HPV 相关的 NADC，从而产生影响，从而提供针对艾滋病毒感染者中日益增加的恶性肿瘤的新干预措施。