Chromosomal Instability as a Marker and Mechanism of Radiation Response

摘要 人类乳头状瘤病毒（HPV）导致全球近5%的癌症，并涉及95%的宫颈癌。 和70%的口咽癌（OPC）。治疗性铂基放化疗是治疗以下疾病的标准 局部晚期宫颈癌和OPC患者，但宫颈癌患者有显着恶化 尽管共享相同的病毒病因，但仍存活。因此，在辐射响应方面存在显著差异 在这两种HPV+癌症之间和之内，我们继续对所有患者进行类似的治疗，而不考虑 个体肿瘤生物学。HPV+和HPV-癌症患者也接受相同的治疗，尽管 两个部位的HPV-癌症的结果显著更差。因此，必须更好地了解 肿瘤生物学，以定制放射治疗，以改善患者的结果，并尽量减少毒性。染色体 不稳定性（CIN）是在多个细胞周期中染色体错误分离事件的持续速率。 分裂，当增加超过一定的阈值时，由于两个拷贝的丢失，可能导致细胞死亡。 一个或多个基本染色体。我们和其他人已经表明，非常高水平的CIN与 在某些癌症中具有细胞死亡、肿瘤抑制和改善的预后。此外，结合两个来源 CIN的增加可使其超过存活阈值，导致细胞死亡。因为HPV和辐射都能诱导 对于某些类型的CIN，我假设预先存在CIN的细胞对辐射更敏感。此外，本发明还 CIN和辐射都可以诱导先天性和适应性免疫应答， 治疗反应，但缺乏预测标志物和机制的见解。该提案旨在：（1）定义 不同HPV基因型和病毒癌基因水平引起的CIN的类型和程度，2）确定是否存在前- 现有的CIN在体外、体内和患者肿瘤中使HPV+和HPV-细胞对辐射敏感，和3）确定 CIN如何影响辐射背景下的先天免疫和适应性免疫。该提案旨在 确定影响放射反应的HPV+和HPV-肿瘤内在和外在因素， 并且宿主生物学可以被结合到放射治疗范例中以降低毒性和增加治愈。 博士科斯特洛是放射肿瘤学的博士后研究员，他将利用这一奖项获得病毒学方面的专业知识， 染色体不稳定性和免疫学，以确定允许个性化的生物标志物， 放疗科布林博士的导师团队由世界知名的HPV病毒学专家组成（保罗博士 Lambert）、CIN（Beth Weaver博士）、头颈癌放射生物学（Randall Kimple博士）和肿瘤 免疫学（Doug McNeel博士）。威斯康星州大学的学术环境一流， 丰富的资源和合作机会。该奖项提供的进一步指导和培训将 为科斯特洛博士提供一套独特的技能，使新的转化研究能够个性化辐射 为头颈癌和宫颈癌患者提供治疗，并成功过渡到独立治疗。 调查员

ABSTRACT Human Papilloma Virus (HPV) causes nearly 5% of all cancers worldwide and is implicated in 95% of cervical and 70% of oropharyngeal cancers (OPC). Curative platinum-based chemoradiation is the standard of care for patients with locally advanced cervical and OPC but patients with cervical cancer have significantly worse survival despite sharing the same viral etiology. Thus, there are significant differences in the radiation response between, and within, these two HPV+ cancers yet we continue to treat all patients similarly without consideration of individual tumor biology. Patients with HPV+ and HPV- cancers are also treated identically despite the significantly worse outcome of HPV- cancers in both sites. It is therefore imperative to gain a better understanding of tumor biology in order to tailor radiotherapy to improve patient outcomes and minimize toxicity. Chromosomal instability (CIN) is an ongoing rate of chromosome missegregation events over the course of multiple cell divisions, and when increased beyond a certain threshold can lead to cell death due to loss of both copies of one or more essential chromosomes. We, and others, have shown that very high levels of CIN are associated with cell death, tumor suppression, and improved prognosis in certain cancers. Moreover, combining two sources of CIN can increase it beyond the viable threshold resulting in cell death. Because both HPV and radiation induce certain types of CIN, I hypothesize that cells with pre-existing CIN will be more sensitive to radiation. Additionally, both CIN and radiation can induce innate and adaptive immune responses which are expected to affect overall treatment response, but predictive markers and mechanistic insights are lacking. This proposal aims to 1) define the types and extent of CIN caused by different HPV genotypes and viral oncogene levels, 2) determine if pre- existing CIN sensitizes HPV+ and HPV- cells to radiation in vitro, in vivo, and in patient tumors, and 3) determine how CIN affects innate and adaptive immunity in the context of radiation. Together, this proposal aims to determine HPV+ and HPV- tumor intrinsic and extrinsic factors that affect radiation response such that tumor and host biology can be incorporated into radiation treatment paradigms to decrease toxicity and increase cure. Dr. Cosper is a post-doctoral fellow in Radiation Oncology and will use this award to gain expertise in virology, chromosomal instability and immunology, in order to determine biomarkers that allow for personalization of radiotherapy. Dr. Cosper’s mentorship team consists of world-renowned experts in HPV virology (Dr. Paul Lambert), CIN (Dr. Beth Weaver), head and neck cancer radiobiology (Dr. Randall Kimple), and tumor immunology (Dr. Doug McNeel). The academic environment at the University of Wisconsin is superb, with abundant resources and collaborative opportunities. Further mentorship and training afforded by this award will provide Dr. Cosper a unique set of skills that will enable novel translational research to personalize radiation treatment for head and neck and cervical cancer patients and result in transition to a successful independent investigator.