XBP1 Inhibition and STING activation for the treatment of cancer

XBP1 抑制和 STING 激活用于癌症治疗

• 批准号: 10606587
• 负责人: Juan R Del Valle
• 金额: $ 56.3万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-08 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606587
• 关键词: Adult; Age; Agonist; Antibodies; Apoptosis; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Lymphocytes; Binding Proteins; Biology; Cell Death; Cell Survival; Cell surface; Cells; Chronic; Chronic Lymphocytic Leukemia; Clinic; Clinical Trials; Cytoplasm; DNA; Data; Deceleration; Development; Diagnosis; Disease; Drug Targeting; Elderly; Engineering; Exhibits; FDA approved; Foundations; Gene Activation; Genes; Growth; Head and Neck Neoplasms; Hematopoietic Neoplasms; Human; Human body; Immune system; Immunity; Immunologic Stimulation; In Vitro; Indolent; Induction of Apoptosis; Infection; Integral Membrane Protein; Interferon Type I; Ligation; Link; Lymphoma; MS4A1 gene; Malignant Neoplasms; Mediating; Methods; Modeling; Monitor; Multiple Myeloma; Mus; Mutate; Names; PD-1 blockade; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Production; Proteins; RNA Splicing; Receptor Signaling; Research; Research Project Grants; Research Project Summaries; Resistance; Solid Neoplasm; Stimulator of Interferon Genes; Stimulus; Testing; Therapeutic; Toxic effect; Tumor Burden; anti-tumor immune response; biological adaptation to stress; cancer cell; cancer therapy; cancer type; cell type; chronic lymphocytic leukemia cell; combat; combinatorial; drug resistance development; endoplasmic reticulum stress; humoral immunity deficiency; in vivo; indexing; inhibitor; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; mouse model; nanobodies; novel; novel therapeutic intervention; pembrolizumab; sortase; synergism

Project Summary This research project focuses on testing and finding cures for patients diagnosed with chronic lymphocytic leukemia (CLL), the most common adult blood cancer. CLL is still an incurable type of cancer derived from B cells, which normally produce antibodies to protect the human body from infections. Although ibrutinib and venetoclax have been approved by the FDA to treat CLL, a large group of CLL patients suffer from chronic toxicities and have to stop using these two drugs. In addition, some CLL patients develop drug resistance and their disease becomes diffuse large B cell lymphoma (DLBCL), which is even harder to treat than CLL. We have shown that both mouse and human CLL cells require activation of a protein called spliced X box-binding protein-1 (XBP-1s) to support their growth and survival. We have developed a drug named B-I09 that can effectively suppress XBP-1 and kill CLL cells. In addition, our new results have shown that CLL cells significantly reduce their expression of a protein called stimulator of interferon genes (STING). Based on our results suggesting that reduced STING in CLL cells may contribute to their survival, we propose to use ADU- S100, a STING activator currently in clinical trials, to stimulate the remaining STING to kill CLL cells. Based on the link between XBP-1s and STING in regulating the same survival mechanism, namely, B cell receptor (BCR) signaling, we propose to test whether B-I09 and ADU-S100 can synergize to kill cultured mouse and human CLL cells. To enable these studies, we have engineered a novel mouse model in which CLL cells produce no STING. We will use this model to test whether ADU-S100 can activate the immune system to synergize with B-I09 to effectively eradicate CLL. Finally, based on our recent progress in successfully developing stimuli-responsive inhibitors of the IRE-1/XBP-1 pathway, we propose to conjugate B-I09 to a single-domain antibody (or nanobody) against human CD20, an integral membrane protein expressed at high levels in CLL cells in order to target the drug to these cells. The resulting nanobody-drug conjugate (NDC) will be evaluated in cells and in vivo for suppression of XBP-1s, reduction of tumor burden, and synergy with ADU- S100 in a novel STING-deficient, human CD20-expresssing CLL mouse model. These studies will serve as the foundation for initiating phase I clinical trials to treat human patients diagnosed with CLL, DLBCL, or potentially other solid tumors with an inhibitor of XBP-1s in combination with an activator of STING. The development of the first NDC to target XBP-1s will open a new and important avenue to enable cell-specific inhibition of XBP- 1s in various cell types as long as such cells express a unique cell surface marker. These novel XBP-1s- targeting NDCs can also be used to interrogate the biology of the IRE-1/XBP-1 pathway in various cell types, and as therapeutics.

项目概要 该研究项目的重点是测试和寻找诊断患有慢性淋巴细胞白血病的患者的治疗方法 白血病（CLL），最常见的成人血癌。 CLL 仍然是一种源自 B 细胞的无法治愈的癌症 细胞，通常会产生抗体来保护人体免受感染。尽管依鲁替尼和 Venetoclax已被FDA批准用于治疗CLL，一大群CLL患者患有慢性 中毒，必须停止使用这两种药物。此外，一些慢性淋巴细胞白血病（CLL）患者会产生耐药性， 他们的疾病变成了弥漫性大 B 细胞淋巴瘤 (DLBCL)，比 CLL 更难治疗。我们 研究表明，小鼠和人类 CLL 细胞都需要激活一种称为剪接 X 盒结合的蛋白质 Protein-1 (XBP-1s) 支持它们的生长和生存。我们开发了一种名为 B-I09 的药物，可以 有效抑制XBP-1并杀死CLL细胞。此外，我们的新结果表明 CLL 细胞 显着降低一种称为干扰素基因刺激物（STING）的蛋白质的表达。基于我们的 结果表明 CLL 细胞中 STING 的减少可能有助于其生存，我们建议使用 ADU- S100是一种STING激活剂，目前正处于临床试验阶段，可刺激剩余的STING杀死CLL细胞。基于 XBP-1 和 STING 之间的联系调节相同的生存机制，即 B 细胞受体 (BCR)信号，我们建议测试B-I09和ADU-S100是否可以协同杀死培养的小鼠和 人类慢性淋巴细胞白血病细胞。为了进行这些研究，我们设计了一种新型小鼠模型，其中 CLL 细胞 不产生 STING。我们将用这个模型来测试ADU-S100是否可以激活免疫系统 与B-I09协同作用，有效根除CLL。最后，基于我们最近成功取得的进展 在开发 IRE-1/XBP-1 通路的刺激响应抑制剂时，我们建议将 B-I09 与 抗人 CD20 的单域抗体（或纳米抗体），CD20 是一种高表达的整合膜蛋白 CLL 细胞中的水平，以便将药物靶向这些细胞。由此产生的纳米抗体-药物缀合物（NDC）将 在细胞和体内评估 XBP-1 的抑制、肿瘤负荷的减少以及与 ADU-的协同作用 新型 STING 缺陷、表达人类 CD20 的 CLL 小鼠模型中的 S100。这些研究将作为 为启动治疗患有 CLL、DLBCL 或潜在疾病的人类患者的 I 期临床试验奠定了基础 使用 XBP-1 抑制剂与 STING 激活剂组合治疗其他实体瘤。的发展 第一个针对 XBP-1 的 NDC 将为 XBP-1 的细胞特异性抑制开辟一条新的重要途径 1s存在于各种细胞类型中，只要这些细胞表达独特的细胞表面标记。这些新颖的 XBP-1s- 靶向 NDC 还可用于研究各种细胞类型中 IRE-1/XBP-1 通路的生物学特性， 并作为治疗方法。