Novel Interventions Against HPV-associated Neoplasia

描述(申请人提供)：人乳头瘤病毒(HPV)是一种感染各种上皮组织的小DNA病毒。肛门生殖器HPV的一个子集，即包括HPV-16和18基因在内的高危HPV，与几乎所有的宫颈癌以及大多数其他肛门生殖器癌和部分头颈癌有关。在美国，每年有超过3万例新癌症是由高危HPV感染引起的。目前治疗这些癌症的方案依赖于几十年前的策略。晚期癌症的五年生存率仍然很低。最近FDA批准的一种HPV疫苗有望预防新的感染，但它要到2040年及以后才会对癌症发病率产生影响。因此，仍然迫切需要开发治疗和/或预防HPV相关癌症的改进方法，从而提高存活率，减少患者的痛苦。这项MMHCC应用的目标是确定治疗和预防HPV阳性癌症的新的、更有效的方案。我们将利用在相关组织中表达HPV16E6和E7癌基因的基因工程小鼠品系作为实现这些目标的临床前模型。这些小鼠已经被用来建立HPV相关的宫颈癌和头颈癌的有效模型。将追求三个主要目标：1)研究抗雌激素在宫颈癌治疗和预防中的使用；2)验证用于治疗HPV相关癌前病变和癌症的激酶靶点；3)开发有效的免疫疗法来治疗HPV相关癌症。

DESCRIPTION (provided by applicant): Human papillomaviruses (HPVs) are small DNA viruses that infect various epithelial tissues. A subset of anogenital HPVs, the 'high risk' HPVs including HPV-16 and 18 genotypes, are associated with nearly all cervical carcinomas, as well as the majority of other anogenital cancers and a subset of head and neck cancers. Each year in the US, over 30,000 new cancers arise from high-risk HPV infections. Current regimens for treating these cancers rely on decades old strategies. Five-year survival rates for advanced grade cancers remain low. A recently FDA-approved HPV vaccine holds promise in preventing new infections, but it will not have an impact on cancer incidence until 2040 and beyond. Therefore there remains an urgent need to develop improved means for treating and/or preventing HPV-associated cancers and thereby increase survival rates and decrease suffering among those afflicted. The goal of this MMHCC application is to identify new, more effective regimens for treating and preventing HPV-positive cancers. We will make use of genetically engineered mouse strains that express the HPV16 E6 and E7 oncogenes in relevant tissues as the preclinical model in which to pursue these goals. These mice have been used to establish well-validated models for HPV associated cervical cancer and head and neck cancers. Three major goals will be pursued: 1) investigate the use of anti-estrogens in the treatment and prevention of cervical cancer, 2) validate kinase targets for therapy of HPV associated premalignant lesions and cancer, and 3) develop effective immunotherapies against HPV-associated cancers.