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

研究细胞衰老对放射治疗疗效的影响。

基本信息

批准号：
10301229
负责人：
Paul Bernard Romesser
金额：
$ 25.5万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10301229
关键词：
Abscopal effect Advisory Committees Antibodies Antitumor Response Biology Cancer Biology Cancer Model Cancer Patient Cell Aging Cell Cycle Arrest Cells Clinical Contralateral DNA Damage Data Dependence Development Plans Distant Educational workshop Effector Cell Environment Epithelial Flow Cytometry Foundations Funding Future Genetic Genetically Engineered Mouse Genotype Goals Growth Human Immune Immunity Immunocompetent Immunophenotyping Immunotherapy Inflammatory Infrastructure Interdisciplinary Study International Ionizing radiation Irradiated tumor Laboratories Malignant Neoplasms Mediating Mediator of activation protein Memorial Sloan-Kettering Cancer Center Mentors Messenger RNA Modality Modeling Multiplexed Ion Beam Imaging Mus Organoids Pathway interactions Patients Phenotype Physicians Positioning Attribute Proteins Radiation Radiation Oncologist Radiation Oncology Radiation Tolerance Radiation therapy Radiobiology Randomized Clinical Trials Rectal Cancer Research Research Personnel Research Project Grants Role Sampling Scientist TP53 gene Testing Therapeutic Tissues Training Tumor-Derived Tumor-infiltrating immune cells Up-Regulation Visualization Work anti-PD-1 anti-PD1 therapy anticancer research antitumor effect base bench to bedside biobank cancer therapy career career development cell type chemokine chemoradiation clinical translation clinically relevant cytokine defined contribution design experience human model immune activation immune checkpoint blockade immunoregulation in situ imaging irradiation mouse model neoplastic cell novel novel strategies novel therapeutics programs radiation effect response senescence single-cell RNA sequencing transcriptome sequencing treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

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.

项目摘要/摘要