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

项目总结/摘要 电离辐射（IR）是一种高效的癌症治疗方法，已知可诱导细胞衰老，即细胞周期 DNA损伤反应引发的逮捕程序细胞衰老导致mRNA的上调 编码分泌因子（包括炎性细胞因子和趋化因子）的程序，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的贡献是未知的。我们的初步数据表明， SASP有助于IR在免疫功能正常的小鼠中的局部和全身抗肿瘤作用， 免疫缺陷小鼠模型。因此，我们假设IR的抗肿瘤作用，无论是局部的还是局部的， 全身性的，部分由SASP通过免疫效应子介导。该项目将使用以下组合 小鼠和人类模型来测试这一假设，并确定辐射的机制， 诱导的SASP改变了局部和远处肿瘤微环境。此外，它还将利用患者肿瘤 样本，以确定接受放疗或化疗的直肠癌患者的临床相关性。 放射与免疫检查点阻断相结合。虽然这项建议的重点是直肠癌， 广泛的临床意义，因为放射治疗是广泛使用的癌症治疗方式。保罗医生 Romesser概述了一个5年的职业计划，该计划建立在他在放射肿瘤学的临床培训和 他的研究背景包括癌症生物学、放射生物学、基因工程小鼠模型， 患者衍生模型。Romesser博士将由国际知名专家Scott Lowe博士指导 在衰老、p53生物学和小鼠建模方面有着良好的培训医生科学家的记录。博士 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 来自一个由杰出的基础科学家、医生科学家和 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， 基础、转化和临床癌症研究的卓越中心。成功完成研究 该项目将导致新的方法来治疗病人的放射治疗，并将提供基础 对于Romesser博士来说，他可以过渡到一个独立的研究者的职位，拥有自己的实验室和R 01 经费

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.