Chromosomal Instability as a Marker and Mechanism of Radiation Response

摘要 人乳头瘤病毒(HPV)导致全球近5%的癌症，95%的宫颈癌与HPV有关 和70%的口咽癌(OPC)。以铂为基础的根治性放化疗是治疗 局部晚期宫颈癌和OPC但宫颈癌患者的病情明显恶化 尽管有相同的病毒病原体，但仍能存活下来。因此，辐射响应存在显著差异。 在这两种HPV+癌症之间和之内，我们继续以同样的方式对待所有患者，而不考虑 个体肿瘤生物学的研究。HPV+和HPV-癌症的患者也得到相同的治疗，尽管 这两个部位的HPV癌症的结果都明显更糟。因此，必须更好地了解 肿瘤生物学的研究，以便量身定做放射治疗，以改善患者的预后并将毒性降至最低。染色体 不稳定(CIN)是多个细胞过程中染色体错误分离事件的持续比率 分裂，当增加超过一定的阈值时，会导致细胞死亡，因为丢失了两个拷贝 一条或多条基本染色体。我们和其他人已经证明，非常高水平的CIN与 在某些癌症中，细胞死亡、肿瘤抑制和预后改善。此外，将两个来源结合起来 CIN可使其增加到超过可存活阈值，导致细胞死亡。因为人乳头瘤病毒和辐射都会引起 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。另外， CIN和辐射都可以诱导先天和获得性免疫反应，预计会影响整体 治疗反应，但缺乏预测性标记和机制洞察力。本提案旨在1)明确 不同的HPV基因型和病毒癌基因水平引起的CIN的类型和程度，2)决定Pre-Pre 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，以及3)确定 CIN如何在辐射背景下影响先天免疫和获得性免疫。总而言之，这项提议旨在 确定影响肿瘤放射反应的HPV+和HPV-肿瘤内在和外在因素 宿主生物学可以被纳入放射治疗的范例中，以减少毒性，提高治愈率。 科斯珀博士是放射肿瘤学博士后，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记物 放射治疗。科斯珀博士的指导团队由世界知名的HPV病毒学专家组成(保罗博士 Lambert)、CIN(Beth Weaver博士)、头颈部癌放射生物学(Randall Kimple博士)和肿瘤 免疫学(道格·麦克尼尔博士)。威斯康星大学的学术环境一流， 丰富的资源和协作的机会。该奖项提供的进一步指导和培训将 为考斯珀博士提供一套独特的技能，使新颖的翻译研究能够个性化辐射 治疗头颈部和宫颈癌患者，并导致过渡到成功的独立 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.