Investigating the contribution of cellular senescence to the efficacy of radiation therapy.

项目摘要/摘要 电离辐射(IR)是一种高效的癌症治疗方法，已知会导致细胞衰老，这是一种细胞周期 DNA损伤反应引发的逮捕程序。细胞衰老导致mRNAs上调 编码分泌因子(包括炎症细胞因子和趋化因子)，这一程序被称为 衰老相关分泌表型(SASP)。SASP调节肿瘤微环境， 它具有多效性免疫调节作用。虽然已知IR敏感性取决于宿主免疫力， 衰老和由此产生的SASP的作用尚不清楚。我们的初步数据表明 SASP在免疫活性方面有助于IR的局部和全身抗肿瘤作用，但不是 免疫缺陷的小鼠模型。因此，我们假设IR的抗肿瘤作用，包括局部和 系统的，部分是由SASP通过免疫效应器调节的。该项目将结合使用 老鼠和人类模型来验证这一假说，并定义辐射- 诱导的SASP改变了局部和远处的肿瘤微环境。此外，它还将使用患者肿瘤 用于确定接受放射治疗或联合治疗的直肠癌患者的临床相关性的样本 放射治疗结合免疫检查站封锁。虽然这项提案关注的是直肠癌，但它已经 广泛的临床意义，因为放射治疗是癌症的一种广泛使用的治疗方式。保罗博士 罗梅瑟概述了他在放射肿瘤学和其他方面的临床培训基础上制定的5年职业计划 他的研究背景包括癌症生物学、辐射生物学、基因工程小鼠模型以及 患者派生的模型。罗梅瑟博士将接受国际知名专家斯科特·洛博士的指导 在衰老、P53生物学和小鼠建模方面，有良好的培训医生和科学家的记录。Dr。 罗梅瑟的职业发展计划包括研究经验、课程工作、研讨会和指导 来自一个跨学科咨询委员会，该委员会由杰出的基础科学家、内科科学家和 放射肿瘤学家。他将得到纪念斯隆·凯特琳癌症中心的支持和基础设施，该中心是 基础、翻译和临床癌症研究的卓越中心。顺利完成研究工作 该项目将带来治疗放射治疗患者的新方法，并将提供基础 对于罗梅瑟博士来说，过渡到拥有自己的实验室和R01的独立研究员的职位 资金问题。

PROJECT SUMMARY/ ABSTRACT Ionizing radiation (IR), a highly effective cancer therapy, is known to induce cellular senescence, a cell cycle arrest program triggered by the DNA damage response. Cellular senescence results in upregulation of mRNAs encoding secreted factors (including inflammatory cytokines and chemokines), a program referred to as the senescence-associated secretory phenotype (SASP). The SASP modulates the tumor microenvironment, and it has pleiotropic immune-modulatory effects. Although IR sensitivity is known to depend upon host immunity, the contribution of senescence and the resultant SASP is unknown. Our preliminary data suggest that the SASP contributes to both localized and systemic anti-tumor effects of IR in immunocompetent, but not immunodeficient, mouse models. Thus, we hypothesize that the anti-tumor effects of IR, both local and systemic, are mediated in part by the SASP through an immune effector. This project will use a combination of mouse and human models to test this hypothesis and to define the mechanisms through which the radiation- induced SASP alters both local and distant tumor microenvironments. In addition, it will use patient tumor samples to establish clinical relevance in patients with rectal cancer treated with radiation therapy or with radiation combined with immune checkpoint blockade. While this proposal focuses on rectal cancer, it has broad clinical implications, as radiation therapy is a widely used treatment modality for cancer. Dr. Paul Romesser has outlined a 5-year career plan that builds upon his clinical training in radiation oncology and on his research background in cancer biology, radiation biology, genetically engineered mouse models, and patient-derived models. Dr. Romesser will be mentored by Dr. Scott Lowe, an internationally renowned expert in senescence, p53 biology, and mouse modeling with a strong track record of training physician-scientists. Dr. Romesser’s career development plan includes research experience, course work, workshops, and mentoring from an interdisciplinary advisory committee comprising distinguished basic scientists, physician-scientists, and radiation oncologists. He will have the support and infrastructure of Memorial Sloan Kettering Cancer Center, a center of excellence in basic, translational, and clinical cancer research. Successful completion of the research project will lead to new approaches for treating patients with radiation therapy and will provide the foundation for Dr. Romesser to transition to a position as an independent investigator with his own laboratory and R01 funding.