Targeting apoptotic caspases to enhance cancer radiotherapy

靶向凋亡半胱天冬酶以增强癌症放射治疗

• 批准号: 10064085
• 负责人: Chuan-Yuan Li
• 金额: $ 46.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-05 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064085
• 关键词: ATP phosphohydrolase; Antibodies; Apoptosis; Apoptotic; Autophagocytosis; Biological; CRISPR/Cas technology; CTLA4 gene; Cancer Patient; Caspase; Caspase Inhibitor; Cells; Charge; Cytotoxic Chemotherapy; Data; Foundations; Genetic; Growth; HMGB1 gene; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; In Vitro; Individual; Knock-out; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular; Mus; Outcome; Patients; Play; Property; Public Health; Publishing; Radiation; Radiation Tolerance; Radiation therapy; Reporting; Research; Role; T-Lymphocyte; Testing; Treatment Efficacy; Treatment outcome; Tumor Immunity; anti-PD1 therapy; anticancer research; base; calreticulin; cancer cell; cancer radiation therapy; cancer therapy; checkpoint therapy; chemotherapy; cytotoxic; immune activation; immunogenic; immunogenic cell death; in situ vaccine; melanoma; neoplastic cell; novel; programmed cell death protein 1; response; small molecule; success; tumor

PROJECT SUMMARY The basis for the success of radiation therapy is long believed to be direct killing and elimination of cancer cells. Therefore, most previous research efforts have focused on enhancing the direct killing effects of radiotherapy. However, recently, it was realized that the host immune system plays key roles in determining the treatment outcome of cytotoxic cancer therapy. In many instances, it has been shown that radiation therapy can activate the immune system to attack cancer cells. However, the molecular mechanisms involved in radiation-induced immune cell activation are poorly understood. In the current project, we intend to test the hypothesis that blockade of certain apoptotic caspases will enhance the efficacy of radiotherapy and immune checkpoint inhibitors by increasing immunogenic cell death. Our hypothesis is based on both published data on the immune-stimulatory effect of radiotherapy and our preliminary data demonstrating strong immunogenic effects of blocking apoptotic caspases. To test our hypothesis, we will attempt to dissect the roles of individual caspases by use of murine tumor cells with CRISPR-Cas9 mediated genetic knockout and evaluating their response to radiotherapy in vitro and in mice (Aim 1). We will then try to identify downstream factors of caspases that are important in radiation induced immunogenic cell death (Aim 2). Finally, we will evaluate if inhibition of caspases is a feasible strategy to enhance radiotherapy in combination with immune- checkpoint inhibitor therapy (Aim 3). Upon completion of our proposed project, we hope to establish the biological roles of apoptotic caspases in immunogenic cell death during radiotherapy and lay the foundation for evaluating caspase inhibitors as potential agents to enhance radiotherapy and immuno-checkpoint inhibitor therapy in human patients.

项目摘要 长期以来，辐射疗法成功的基础是直接杀害和消除 癌细胞。因此，大多数以前的研究工作都集中于增强直接杀戮 放疗的作用。但是，最近，人们意识到宿主免疫系统发挥关键 在确定细胞毒性癌症治疗的治疗结果中的作用。在许多情况下，已经 表明放射治疗可以激活免疫系统以攻击癌细胞。但是， 涉及辐射诱导的免疫细胞激活的分子机制知之甚少。 在当前的项目中，我们打算检验以下假设，即某些凋亡胱天蛋白酶的阻塞 将通过增加放疗和免疫检查点抑制剂的功效 免疫原性细胞死亡。我们的假设是基于有关免疫刺激性的两个已发表数据 放射疗法的影响和我们的初步数据表明阻塞的强烈免疫原性作用 凋亡的胱天蛋白酶。 为了检验我们的假设，我们将尝试通过使用鼠类来剖析单个胱天蛋白酶的作用 具有CRISPR-CAS9介导的遗传基因敲除的肿瘤细胞，并评估其对 体外和小鼠放疗（AIM 1）。然后，我们将尝试识别胱天蛋白酶的下游因素 在辐射引起的免疫原性细胞死亡中很重要（AIM 2）。最后，我们将评估是否 抑制胱天蛋白酶是一种可行的策略，可以增强放射疗法与免疫 - 检查点抑制剂疗法（AIM 3）。 我们提出的项目完成后，我们希望确定凋亡的生物学作用 放射治疗期间免疫原性死亡中的胱天蛋白酶酶，并为评估caspase奠定基础 抑制剂作为增强放疗和免疫检查抑制剂治疗的潜在药物 人类患者。