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

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，且具有耐药性， 无论是内在的还是后天的，都是一个关键问题。因此，阐明贫困的发病机制势在必行。 对西妥昔单抗的反应和制定策略以增强肿瘤对西妥昔单抗的反应并改善患者 结果。我的整个研究兴趣都围绕着炎症和免疫反应作为关键 HNSCC患者肿瘤进展机制和西妥昔单抗对肿瘤的不良反应。我的论文 研究重点是IL-1通路在HNSCC西妥昔单抗肿瘤反应中的重要作用 患者和我的论文研究的总体假设是，IL-1阻断将提高抗- 西妥昔单抗治疗HNSCC的肿瘤疗效。到目前为止，我的学位论文研究项目取得了很强的成果 支持这一假设，表明使用中和IL-1α(IL-1α)抗体的IL-1阻断增加 西妥昔单抗对小鼠肝细胞癌移植瘤的反应及IL-1α可能是 预测西妥昔单抗对HNSCC患者肿瘤疗效的生物标记物。在我毕业论文的剩余部分 研究项目中，我将继续使用FDA批准的IL-1受体拮抗剂(IL-1)来验证我的假设 1ra)Anakinra联合西妥昔单抗治疗HNSCC小鼠模型，并评估其可能的作用机制 肿瘤对联合用药的反应。最后，在我的博士后期间，我对 抗IL-1联合抗CTLA4/PD1治疗HNSCC 包括HNSCC的目的是使用抗CTLA4/PD1疗法激活免疫系统。总的来说，我认为这一点 F99/K00奖将帮助我建立专注于炎症和免疫的研究生涯 作为肿瘤药物治疗反应的重要参与者，并为我成为一名 成功的独立调查员。

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.