DNA Damage and Immunogenicity in Ewing Sarcoma

尤文肉瘤中的 DNA 损伤和免疫原性

• 批准号: 10360543
• 负责人: Kelly Bailey
• 金额: $ 15.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360543
• 关键词: Activated Lymphocyte; Address; Adolescent; Advanced Malignant Neoplasm; Agonist; Animal Model; Antineoplastic Protocols; Antitumor Response; Area; Authorship; Automobile Driving; BARD1 gene; BRCA1 gene; Bioinformatics; CD8-Positive T-Lymphocytes; Cancer Biology; Cell Surface Proteins; Cell model; Cells; Cellular biology; Childhood Cancer Treatment; Chimeric Proteins; Coculture Techniques; Combination immunotherapy; Combined Modality Therapy; Committee Members; Complement; Computer Analysis; Cyclic GMP; DNA; DNA Damage; DNA Repair; Data; Defect; Development Plans; Diagnosis; Doxorubicin; EWS-FLI1 fusion protein; Educational Status; Educational workshop; Environment; Ewings sarcoma; Feedback; Fostering; Gene Activation; Germ-Line Mutation; Goals; Grant; Growth; Human; IRF1 gene; Immune; Immune checkpoint inhibitor; Immune response; Immunobiology; Immunology; Immunotherapeutic agent; Immunotherapy; Impairment; In Vitro; Individual; Infiltration; Inflammatory; Interferon Activation; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Literature; Location; Malignant Bone Neoplasm; Malignant Childhood Neoplasm; Malignant Neoplasms; Manuscripts; Mediating; Mentors; Mutation; Oncogenic; Pathway interactions; Patients; Pediatric Oncologist; Pediatric Oncology; Physicians; Poly(ADP-ribose) Polymerases; Radiation; Regulation; Relapse; Research; Sampling; Science; Scientist; Seasons; Signal Transduction; Specimen; Stimulator of Interferon Genes; T cell response; T-Lymphocyte; Technical Expertise; Techniques; Testing; Training; Training Technics; Tumor Cell Biology; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Universities; Up-Regulation; Vocational Guidance; Woman; Work; anti-tumor immune response; anticancer research; base; cancer cell; career; career development; checkpoint inhibition; checkpoint therapy; cytokine; cytotoxic CD8 T cells; efficacy evaluation; gene repair; homologous recombination; humanized mouse; immune checkpoint; immunogenicity; immunoregulation; improved; in vivo; inhibitor; malignant breast neoplasm; meetings; mouse model; neoplastic cell; patient subsets; pre-clinical; programmed cell death ligand 1; programs; recruit; repair function; response; skills; tumor; tumor DNA; tumor immunology; tumor-immune system interactions

The goal of this career development award is for the applicant to expand her knowledge and technical expertise in tumor immunology and bioinformatic analyses in order to apply these new skills to investigation of the childhood cancer Ewing sarcoma. Relapsed Ewing sarcoma is nearly uniformly fatal, and thus new treatment approaches are desperately needed. A growing number of immune-based therapies are now being incorporated into pediatric cancer treatment protocols. Thus, in order to be a successful clinician scientist directing a cutting- edge research program in Ewing sarcoma, it is essential that the applicant gain expertise in tumor immunobiology. Currently, very little is understood about regulation of the Ewing sarcoma tumor immune microenvironment. This proposal addresses the interplay of two broadly important facets of pediatric cancer research: DNA damage repair and tumor immune response. This proposed work specifically examines the ability of DNA damage to activate Ewing tumor cell immunoregulatory pathways. The proposed aims will utilize a combination of in vitro cell co-culture analyses, in vivo tumor animal modeling and human specimen analyses in order to address this important topic. The applicant has chosen a primary mentor who is an expert in immune/inflammatory signaling in cancer, and a co-mentor with expertise in T-cell biology and advanced immunology techniques. Additionally, the applicant has constructed a physician-scientist career mentoring committee and network of collaboartors including individuals with expertise in Ewing sarcoma, humanized mouse models, DNA damage repair, the tumor immune-microenvironment, and bioinformatic analyses. As a team, the mentor, co-mentor, committee members and collaborators are dedicated to providing the applicant with technique training in tumor immunology and advanced cancer biology, as well as critical feedback on grants and manuscripts and career guidance. The primary mentor and co-mentor are invested in guiding the applicant toward a highly successful career as physician scientist by transitioning her to senior authorship on manuscripts, preparing her to start an independent laboratory and encouraging her to directly mentor scientists and clinicians at various levels of training. The University of Pittsburgh is an outstanding environment in which to develop a career and expand a research program in tumor immunobiology. The applicant’s career development plan takes full advantage of the many unique offerings at Pittsburgh including face-to-face career development workshops with seasoned scientists, participation in the Pittsburgh Women in Science forum, graduate level tumor immunobiology and bioinformatics courses and opportunities for presentation of work-in-progress at the University of Pittsburgh Cancer Immunology Program meetings. With the enthusiastic support and exceptional scientific expertise of her mentor and co-mentor, the applicant is eager to gain specific training in tumor immunobiology and bioinformatic analyses and to launch an independent research career as a pediatric oncologist physician scientist studying Ewing sarcoma at the University of Pittsburgh.

该职业发展奖的目标是让申请人扩展其知识和技术专长 肿瘤免疫学和生物信息分析，以便将这些新技能应用于研究 儿童癌症尤文肉瘤。复发的尤文肉瘤几乎都是致命的，因此新的治疗方法 迫切需要采取一些方法。现在正在纳入越来越多的基于免疫的疗法 纳入儿科癌症治疗方案。因此，为了成为一名成功的临床科学家，指导切割 尤文肉瘤的边缘研究项目，申请人获得肿瘤方面的专业知识至关重要 免疫生物学。目前，人们对尤文肉瘤肿瘤免疫的调节知之甚少。 微环境。该提案解决了儿科癌症两个广泛重要方面的相互作用 研究方向：DNA损伤修复与肿瘤免疫反应。这项拟议的工作专门考察了能力 DNA损伤激活尤文肿瘤细胞免疫调节途径。拟议的目标将利用 结合体外细胞共培养分析、体内肿瘤动物模型和人体样本分析 为了解决这个重要的话题。申请人选择了一位主要导师，他是以下领域的专家 癌症中的免疫/炎症信号传导，以及具有 T 细胞生物学和高级专业知识的共同导师 免疫学技术。此外，申请人还建立了医师科学家职业指导 委员会和合作者网络，包括具有尤文肉瘤、人源化小鼠专业知识的个人 模型、DNA 损伤修复、肿瘤免疫微环境和生物信息学分析。作为一个团队， 导师、共同导师、委员会成员和合作者致力于为申请人提供 肿瘤免疫学和先进癌症生物学方面的技术培训，以及对拨款和资助的关键反馈 手稿和职业指导。主要导师和共同导师致力于指导申请人 通过将她转变为手稿的高级作者，走向作为医学科学家的高度成功的职业生涯， 为她建立一个独立实验室做好准备，并鼓励她直接指导科学家和临床医生 在不同级别的培训中。匹兹堡大学为培养人才提供了优越的环境 职业生涯并扩大肿瘤免疫生物学的研究项目。申请人的职业发展计划需要 充分利用匹兹堡的许多独特服务，包括面对面的职业发展研讨会 与经验丰富的科学家一起，参加匹兹堡女性科学论坛，研究生水平肿瘤 免疫生物学和生物信息学课程以及在会议上展示正在进行的工作的机会 匹兹堡大学癌症免疫学项目会议。凭借热情的支持和卓越的 由于她的导师和共同导师的科学专业知识，申请人渴望获得肿瘤方面的具体培训 免疫生物学和生物信息分析，并以儿科身份开展独立的研究生涯 匹兹堡大学研究尤文肉瘤的肿瘤学家医师科学家。