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.

项目摘要 该研究项目的重点是针对诊断患有慢性淋巴细胞的患者进行测试和寻找治疗方法 白血病（CLL），最常见的成人血液癌。 CLL仍然是源自B的一种无法治愈的癌症 通常产生抗体以保护人体免受感染的细胞。虽然ibrutinib和 Venetoclax已获得FDA的批准来治疗CLL，一大批CLL患者患有慢性病 毒性，必须停止使用这两种药物。此外，一些CLL患者会产生耐药性和 它们的疾病变得弥漫性大B细胞淋巴瘤（DLBCL），比CLL更难治疗。我们 已经表明，小鼠和人类CLL细胞都需要激活称为剪接的X盒结合的蛋白质 蛋白-1（XBP-1）支持其生长和生存。我们已经开发了一种名为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 显着降低了它们的表达，称为干扰素基因的刺激剂（STING）。基于我们 结果表明，CLL细胞中刺激的降低可能有助于其生存，我们建议使用ADU- S100是目前正在临床试验中的刺激激活剂，可刺激其余的刺痛以杀死CLL细胞。基于 XBP-1S与刺痛之间的联系在调节相同的生存机制中，即B细胞受体 （bcr）发出信号，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CLL细胞。为了实现这些研究，我们设计了一种新型的小鼠模型，其中CLL细胞 不产生刺痛。我们将使用此模型测试ADU-S100是否可以激活免疫系统 与B-I09协同作用，有效地消除了CLL。最后，根据我们最近成功的进展 开发IRE-1/XBP-1途径的刺激响应性抑制剂，我们建议将B-I09结合到A 针对人CD20的单域抗体（或纳米型），一种在高高表示的整合性膜蛋白 CLL细胞中的水平将药物靶向这些细胞。由此产生的纳米毒剂 - 药物缀合物（NDC）将 在细胞和体内进行评估，以抑制XBP-1，减轻肿瘤负担以及与ADU的协同作用 S100在一种新型的缺陷，人CD20表达CLL小鼠模型中。这些研究将作为 启动I期临床试验的基础，以治疗被诊断为CLL，DLBCL或潜在的患者 其他具有XBP-1抑制剂的实体瘤与STING活化剂结合使用。发展的发展 第一个针对XBP-1S的NDC将开辟一条新的重要途径，以实现细胞特异性抑制XBP- 只要这样的细胞表达独特的细胞表面标记，各种细胞类型中的1s即可。这些新颖的XBP-1-- 靶向NDC也可以用于询问各种细胞类型中IRE-1/XBP-1途径的生物学， 作为治疗学。