XBP1 Inhibition and STING activation for the treatment of cancer

项目摘要 该研究项目的重点是测试和寻找治愈慢性淋巴细胞性白血病患者的方法。 白血病（CLL）是最常见的成人血癌。CLL仍然是一种无法治愈的类型的癌症来源于B 细胞，通常产生抗体以保护人体免受感染。虽然伊鲁替尼和 维奈托克已被FDA批准用于治疗CLL，一大群CLL患者患有慢性炎症， 有毒性，必须停止使用这两种药物。此外，一些CLL患者产生耐药性， 他们的疾病变成弥漫性大B细胞淋巴瘤（DLBCL），其甚至比CLL更难治疗。我们 已经表明小鼠和人类CLL细胞都需要激活一种称为剪接X盒结合的蛋白质 蛋白-1（XBP-1 s）来支持它们的生长和存活。我们开发了一种名为B-I 09的药物， 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 显著降低了一种称为干扰素基因刺激因子（STING）的蛋白质的表达。基于我们 结果表明CLL细胞中STING的减少可能有助于其存活，我们建议使用ADU- S100，目前在临床试验中的STING激活剂，以刺激剩余的STING杀死CLL细胞。基于 XBP-1 s和STING在调节相同的存活机制即B细胞受体方面的联系 (BCR)信号转导，我们建议测试B-I 09和ADU-S100是否可以协同杀死培养的小鼠， 人CLL细胞。为了使这些研究成为可能，我们设计了一种新的小鼠模型，其中CLL细胞 不产生刺痛。我们将使用这个模型来测试ADU-S100是否可以激活免疫系统， 与B-I 09协同有效根除CLL。最后，根据我们最近的进展， 为了开发IRE-1/XBP-1通路的刺激响应性抑制剂，我们建议将B-I 09与 抗人CD 20的单域抗体（或纳米抗体），人CD 20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。所得纳米抗体-药物缀合物（NDC）将 在细胞和体内评价XBP-1的抑制、肿瘤负荷的减少以及与ADU的协同作用。 S100在新型STING缺陷、表达人CD 20的CLL小鼠模型中的作用这些研究将作为 启动I期临床试验的基础，以治疗诊断为CLL，DLBCL或潜在的人类患者 与XBP-1抑制剂和STING激活剂组合的其它实体瘤。的发展 第一个靶向XBP-1的NDC将开辟一条新的重要途径，使XBP的细胞特异性抑制成为可能。 1 s，只要这些细胞表达独特的细胞表面标志物。这些新型XBP-1 靶向NDC也可用于询问各种细胞类型中IRE-1/XBP-1途径的生物学， 和作为治疗剂。

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.