Compartimental bi-specific antibody and cytokine therapy for advance desmoplastic small round cell tumors

房室双特异性抗体和细胞因子治疗晚期促结缔组织增生性小圆细胞肿瘤

• 批准号: 10379234
• 负责人: Madelyn Espinosa-Cotton
• 金额: $ 10.46万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379234
• 关键词: Antibodies; Antibody Therapy; Area; Award; Biological Markers; Bispecific Antibodies; CTLA4 gene; Cell Survival; Cell physiology; Cells; Cetuximab; Combination Drug Therapy; Data; Data Set; Desmoplastic Small Round Cell Tumor; Doctor of Philosophy; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; FDA approved; Flow Cytometry; Gene Expression; Genes; Genetic; Goals; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immune response; Immune system; Immunocompetent; In Vitro; Inflammation; Inflammatory; Innate Immune Response; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 alpha; Interleukin-6; Interleukin-8; Knowledge; Link; Malignant Epithelial Cell; Modality; Neoplasm Metastasis; Oxidation-Reduction; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacotherapy; Play; Production; Prognosis; Reactive Oxygen Species; Recombinants; Research; Research Personnel; Research Project Grants; Resistance; Rheumatoid Arthritis; Role; Schools; Serum; Signal Transduction; T-Lymphocyte; Testing; The Cancer Genome Atlas; Translating; Tumor Promotion; Work; Xenograft procedure; adaptive immune response; anakinra; angiogenesis; antagonist; anti-CTLA4; cancer cachexia; cancer therapy; career; cell growth; cytokine; cytokine therapy; effective therapy; improved; interest; knock-down; mouse model; neoplastic cell; novel therapeutics; overexpression; pre-clinical; programmed cell death protein 1; recruit; response; skills; trend; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor progression

Project Summary Overall response to the epidermal growth factor receptor (EGFR) inhibitor cetuximab is poor and resistance, both intrinsic and acquired, is a critical issue. Therefore it is imperative to elucidate the mechanisms of poor response to cetuximab and develop strategies to enhance tumor response to cetuximab and improve patient outcomes. My overall research interests center around inflammation and immune response as key mechanisms of tumor progression in HNSCC patients and poor tumor response to cetuximab. My dissertation research focuses on the IL-1 pathway as an important player in tumor response to cetuximab in HNSCC patients and the overall hypothesis of my dissertation research is that IL-1 blockade will improve the anti- tumor efficacy of cetuximab in HNSCC. Findings from my dissertation research project thus far strongly support this hypothesis indicating that IL-1 blockade using a neutralizing IL-1 alpha (IL-1α) antibody increased HNSCC tumor response to cetuximab in xenograft mouse models and that IL-1α may be an important biomarker to predict tumor response to cetuximab for HNSCC patients. For the remainder of my dissertation research project, I will continue to test my hypothesis using the FDA approved IL-1 receptor antagonist (IL- 1RA) anakinra in combination with cetuximab in HNSCC mouse models, and assess potential mechanisms of tumor response to combination drug therapy. Finally, during my postdoctoral period I am interested in combining anti-IL-1 therapy with anti-CTLA4/PD1 therapy for HNSCC since the current trend in cancer therapy including HNSCC is to activate the immune system using anti-CTLA4/PD1 therapies. Overall, I believe that this F99/K00 award will assist me in establishing my research career focused on inflammation and immune response as important players in tumor response to drug therapy and pave the way for me to become a successful independent investigator.

项目摘要 对表皮生长因子受体（EGFR）抑制剂西妥昔单抗的总体反应较差， 无论是内在的还是后天的，都是一个关键问题。因此，必须阐明贫困的机制， 西妥昔单抗的反应，并制定策略，以提高肿瘤对西妥昔单抗的反应， 结果。我的总体研究兴趣围绕炎症和免疫反应为关键 HNSCC患者的肿瘤进展机制和对西妥昔单抗的不良肿瘤应答。我的论文 研究重点是IL-1通路在HNSCC中对西妥昔单抗的肿瘤应答中的重要作用 患者和我的论文研究的总体假设是，IL-1阻断将改善抗- 西妥昔单抗在HNSCC中的肿瘤疗效我的论文研究项目的结果到目前为止强烈 支持这一假设，表明使用中和IL-1 α（IL-1α）抗体的IL-1阻断增加了 异种移植小鼠模型中HNSCC肿瘤对西妥昔单抗的反应，IL-1α可能是重要的免疫调节因子。 用于预测HNSCC患者对西妥昔单抗的肿瘤反应的生物标志物。在我论文的剩余部分 研究项目，我将继续测试我的假设使用FDA批准的IL-1受体拮抗剂（IL- 1 RA）阿那白滞素与西妥昔单抗组合在HNSCC小鼠模型中的作用，并评估 肿瘤对联合药物治疗的反应。最后，在我的博士后期间，我感兴趣的是 由于目前癌症治疗的趋势，将抗IL-1治疗与抗CTLA 4/PD 1治疗相结合用于HNSCC 包括HNSCC在内的免疫治疗的目的是使用抗CTLA 4/PD 1疗法激活免疫系统。总的来说，我认为， F99/K 00奖将帮助我建立我的研究生涯，专注于炎症和免疫 作为肿瘤对药物治疗反应的重要参与者，为我成为一名 成功的独立调查员