Chromosomal Instability as a Marker and Mechanism of Radiation Response

染色体不稳定性作为辐射反应的标志和机制

• 批准号: 10656230
• 负责人: Pippa F Cosper
• 金额: $ 18.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656230
• 关键词: Affect; Aneuploidy; Award; Biological Markers; Biology; Cancer Model; Cancer Patient; Cell Death; Cell Line; Cell division; Cells; Cervical; Chromosomal Instability; Chromosomal Stability; Chromosomes; Clinical; DNA; Data; Dose; Engineering; Environment; Epithelial Cells; Etiology; Event; Exhibits; Genotype; Glioma; Haploidy; Head and Neck Cancer; Human; Human Papilloma Virus Vaccine; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Human papillomavirus 18; Immune; Immune response; Immunocompetent; Immunologic Markers; Immunology; In Vitro; Incidence; Individual; Innate Immune Response; Interferon Type I; Ionizing radiation; Laboratories; Length; Locally Advanced Malignant Neoplasm; Lymphocytic Infiltrate; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mentorship; Mitotic; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Oral; Oropharyngeal; Outcome; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Platinum; Postdoctoral Fellow; Prognosis; Radiation; Radiation Oncology; Radiation Tolerance; Radiation therapy; Radiobiology; Rectal Cancer; Recurrence; Research Personnel; Resources; Sampling; Site; Source; Stimulator of Interferon Genes; Testing; Time; Tonsil; Toxic effect; Training; Translating; Translational Research; Tumor Biology; Tumor Immunity; Tumor Promotion; Tumor Suppression; Universities; Viral; Viral Oncogene; Wisconsin; adaptive immune response; adaptive immunity; advanced disease; alternative treatment; anti-tumor immune response; cancer cell; chemoradiation; chromosome missegregation; chromosome number abnormality; clinically relevant; cohort; head and neck cancer patient; immunogenic; improved; in vitro Assay; in vivo; insight; keratinocyte; malignant oropharynx neoplasm; novel; oral HPV-positive head and neck cancers; personalized medicine; predictive marker; radiation response; response; skills; standard of care; treatment response; tumor; tumor growth; tumor immunology; virology

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.

抽象的 人类乳头状瘤病毒（HPV）在全球所有癌症中近5％，并在95％的宫颈中实施 和70％的口咽癌（OPC）。基于铂的化学放疗是护理的标准 患有局部晚期宫颈和OPC的患者，但宫颈癌患者明显恶化 生存目的地共享相同的病毒病因。这，辐射响应存在显着差异 在这两个HPV+癌症之间和内部之间，但我们继续同样对所有患者进行类似的治疗 单个肿瘤生物学。 HPV+和HPV-Cancers的患者也接受了相同的治疗 两个站点中HPV-Canters的结果明显较差。因此，必须更好地理解 肿瘤生物学以量身定制放疗以改善患者的预后并最大程度地减少毒性。染色体 不稳定性（CIN）是多个细胞过程中染色体错误播种事件的持续率 分裂，并且由于两种副本的丢失而增加了一定阈值，可能会导致细胞死亡 一个或多个必需的染色体。我们和其他人表明，很高的CIN是相关的 通过细胞死亡，肿瘤抑制和某些癌症的预后改善。此外，结合了两个来源 CIN可以将其增加超出可行的阈值，从而导致细胞死亡。因为HPV和辐射影响 某些类型的CIN，我假设具有预先存在CIN的细胞对辐射更敏感。此外， CIN和辐射都可以诱导先天和适应性免疫回报，这有望影响整体 治疗反应，但缺乏预测标记和机理见解。该建议的目的是1）定义 由不同的HPV基因型和病毒性癌基水平引起的CIN的类型和程度，2）确定是否预先 现有CIN在体外，体内和患者肿瘤中感应HPV+和HPV细胞对辐射的感觉，3）确定 CIN在辐射的背景下如何影响先天和适应性免疫。该提议共同旨在 确定影响辐射反应的HPV+和HPV-肿瘤的内在和外在因素，以使肿瘤 可以将宿主生物学纳入放射治疗范式中，以降低毒性并增加治疗。 Cosper博士是放射肿瘤学的博士后研究员，将使用该奖项来获得病毒学专业知识， 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。 Cosper博士的Mentalship团队由HPV病毒学的世界知名专家组成（Paul博士 兰伯特（Lambert），CIN（Beth Weaver博士），头颈癌放射生物学（Randall Kinple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很棒， 最丰富的资源和协作机会。该奖项提供的进一步的精通和培训将 为Cosper博士提供一套独特的技能，这些技能将使新颖的翻译研究能够个性化辐射 头颈和宫颈癌患者的治疗，导致过渡到成功的独立 研究者。