Mechanisms of STING in malignant progression and therapy of CLL.

STING 在 CLL 恶性进展和治疗中的机制。

• 批准号: 10582290
• 负责人: Chih-Chi Andrew Hu
• 金额: $ 49.21万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582290
• 关键词: Acceleration; Adjuvant; Adverse effects; Agammaglobulinaemia tyrosine kinase; Agonist; Apoptosis; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Lymphocytes; Binding; Cells; Cessation of life; Chemoresistance; Chronic; Chronic Lymphocytic Leukemia; Clinic; Clinical Trials; Combination immunotherapy; Complex; Cytoplasm; DNA; Data; Databases; Drops; Endoplasmic Reticulum; Gene Activation; Gene Expression; Genes; Genetic; Growth; Human; Human Characteristics; IRF3 gene; Immune response; Immunologic Deficiency Syndromes; Induction of Apoptosis; Inflammatory; Injections; Interferon Type I; Interferons; Knockout Mice; Lewis Lung Carcinoma; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical; Mitochondria; Multiple Myeloma; Mus; Mutation; National Cancer Institute; PD-1 blockade; Patients; Phosphorylation; Primary carcinoma of the liver cells; Production; Proteins; Radiation; Receptor Signaling; Resistance; Role; Sampling; Serine; Signal Transduction; Solid Neoplasm; Stimulator of Interferon Genes; T cell response; TBK1 gene; Testing; Therapeutic; Tumor Immunity; Tyrosine Kinase Inhibitor; United States; Work; adult leukemia; biomarker selection; cancer regression; cell growth; cell type; chronic lymphocytic leukemia cell; cytokine; cytotoxicity; gene repression; humoral immunity deficiency; in vivo; inhibitor; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; leukemic transformation; lung cancer cell; melanoma; mouse model; novel; novel therapeutics; patient derived xenograft model; pembrolizumab; targeted treatment; tumor

Project Summary/Abstract Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia and is still incurable. According to the National Cancer Institute, approximately 21,250 new cases of CLL and 4,320 deaths from CLL are projected in the United States alone in 2021. Although the Bruton's tyrosine kinase inhibitor (BTKi) is an effective targeted therapy for CLL, approximately 50% of BTKi-treated CLL patients have dropped out of the therapy due to chronic adverse effects. Additionally, significantly increased numbers of CLL patients treated with BTKi or other kinase inhibitors have developed the more medically challenging diffuse large B cell lymphoma. Novel therapy that can directly target CLL or be rationally combined with BTKi is highly desirable. The stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-resident protein critical for sensing cytoplasmic DNA and promoting production of type I interferons, thereby boosting immune responses. STING agonists, such as ADU-S100, have been used as combination immunotherapy with Pembrolizumab in clinical trials to treat advanced solid tumors and lymphomas, and these therapeutic applications of STING agonists are based on the main known function of STING in eliciting anti-tumor immunity. We were the first to show that STING agonists directly induce potent mitochondria-mediated apoptosis in B cell-derived malignancies including CLL, while these agonists induce production of interferons in melanoma, hepatoma and lung cancer cells without suppressing their growth. Apoptosis of CLL, B cell lymphoma and multiple myeloma requires STING, because genetic deletion of STING results in resistance of all these cells to STING agonist-mediated apoptosis. Apoptosis of these cells is not due to the production of inflammatory cytokines but may involve the prolonged presence of agonist-bound STING. Together with our new preliminary results showing that mutation-mediated activation of STING causes rapid degradation of the B cell receptor (BCR) and significantly reduced BCR signaling (disadvantageous for CLL survival), and that novel serine residues on STING are phosphorylated in agonist-stimulated malignant B cells, we propose to identify and characterize differential phosphorylation and interacting partners of activated STING to further understand the mechanisms by which activated STING causes BCR degradation and apoptosis in CLL. Since our preliminary data show that STING deficiency can lead to increased levels of the BCR and BCR signaling in mouse CLL, and that mouse and human malignant CLL cells significantly downregulate their expression levels of STING, we will test whether STING- downregulated or STING-deficient CLL cells are less sensitive to BTKi. We will also examine how such altered STING expression and phosphorylation can regulate the survival, progression and chemoresistance of CLL. Based on our hypothesis that activation of STING can lead to the degradation of the BCR and render CLL cells more sensitive to BTKi, we propose to combine STING agonists with BTKi to treat CLL.

项目摘要/摘要 慢性淋巴细胞白血病（CLL）代表成人白血病的30％，仍然无法治愈。根据 全国癌症研究所，约有21,250例CLL的新病例和4,320例死亡。 仅美国就在2021年。尽管布鲁顿的酪氨酸激酶抑制剂（BTKI）是有效的目标 CLL治疗，大约50％的BTKI治疗的CLL患者由于 慢性不良反应。此外，用BTKI或其他治疗的CLL患者数量显着增加 激酶抑制剂已经发展出更具挑战性的弥漫性大B细胞淋巴瘤。新疗法 可以直接靶向CLL或与BTKI合理结合。干扰素的刺激器 基因（STING）是一种内质网（ER） - 驻留蛋白，对于感测细胞质DNA和 促进I型干扰素的产生，从而增强免疫反应。刺痛者，例如 在临床试验中，ADU-S100已用作pembrolizumab的联合免疫疗法以治疗 晚期实体瘤和淋巴瘤，以及刺痛的这些治疗应用是基于 Sting在引发抗肿瘤免疫力中的主要已知功能。我们是第一个表明sting的人 激动剂直接诱导B细胞衍生的恶性肿瘤（包括CLL）的有效线粒体介导的凋亡 这些激动剂诱导黑色素瘤，肝癌和肺癌细胞中的干扰素产生 抑制他们的成长。 CLL，B细胞淋巴瘤和多发性骨髓瘤的凋亡需要刺痛，因为 刺痛的遗传缺失导致所有这些细胞对刺激性激动剂介导的细胞凋亡的抗性。 这些细胞的凋亡不是由于炎症细胞因子的产生，而是涉及延长的 存在激动剂的刺痛。加上我们的新初步结果，表明突变介导 刺激的激活导致B细胞受体（BCR）的快速降解，并显着降低了BCR 信号传导（对于CLL存活不利），并且在刺痛的新型丝氨酸残基被磷酸化 激动剂刺激的恶性B细胞，我们建议识别和表征差异磷酸化和表征 激活刺痛的互动伙伴，以进一步了解激活刺痛的机制 导致BCR降解和CLL凋亡。由于我们的初步数据表明，刺痛的缺陷可以 导致小鼠CLL中BCR和BCR信号的水平增加，而小鼠和人类恶性肿瘤 CLL细胞显着下调其刺痛的表达水平，我们将测试是否sting- 下调或缺陷的CLL细胞对BTKI敏感。我们还将研究这种改变 刺激表达和磷酸化可以调节CLL的存活，进展和化学抗性。 基于我们的假设，即刺激的激活会导致BCR的降解并渲染CLL细胞 对BTKI更敏感，我们建议将刺痛的激动剂与BTKI相结合以治疗CLL。