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

项目总结/摘要 HPV相关非AIDS定义癌症的新型靶向治疗（生物样本/生物队列） 非艾滋病定义的癌症（NADC）在艾滋病毒感染者（HIVII）中的发病率正在增加， 治疗干预的发展。许多与艾滋病毒相关的癌症是与以下疾病合并感染的结果： 人乳头瘤病毒（HPV）是一种常见的致癌病毒，高危型人乳头瘤病毒（HPV）在几种肿瘤的发展中普遍存在。 NADC，包括头颈部（HNC）和肛门癌。重要的是，HPV病毒癌基因参与 在这些癌症的转化和维持中，被认为是HPV相关性肿瘤的独特靶点。 恶性肿瘤。这些病毒基因通常被认为是"坚不可摧的"，对靶向基因治疗很敏感 我们已经开发出一种新的，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递送系统，我们以前曾用于 基于RNA的治疗剂的体内递送。重要的是，尽管HPV癌基因代表了存活的 治疗靶点，没有研究调查靶向病毒的潜在抗增殖作用。 体内来自HIVIIs的HPV相关肿瘤中的癌基因。我们的长期目标是发展创新 治疗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阻遏物使NADC中的HPV癌基因失活。根据我们的初步数据， 和专业知识，使用靶向阻遏物和纳米颗粒输送系统，我们提出了两个互补的，但 不同的目的，1）表征新的，有效的ZFP阻遏物在HPV中的抗增殖作用， 与NADC相关的相关细胞系模型，和2）评估LNP递送的抗HPV效应物以抑制 在患者来源的异种移植（PDX）鼠模型中来自HIVII的HPV相关HNC。总的来说，这项工作 将通过开发一种创新的靶向阻遏物来抑制HPV相关的NADC， 对HIV感染者恶性肿瘤增加的新干预措施。

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.