XBP1 Inhibition and STING activation for the treatment of cancer

项目摘要 这项研究项目的重点是检测和寻找慢性淋巴细胞症患者的治疗方法。 白血病(CLL)，最常见的成人血癌。慢性淋巴细胞性白血病仍然是一种源于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。虽然伊布鲁替尼和安慰剂 万乃馨已被FDA批准用于治疗CLL，一大批慢性CLL患者 毒副作用，必须停止使用这两种药物。此外，一些慢性淋巴细胞性白血病患者会产生抗药性和 他们的疾病变成弥漫性大B细胞淋巴瘤(DLBCL)，比CLL更难治疗。我们 已经表明，小鼠和人类的CLL细胞都需要一种名为剪接X盒结合的蛋白质的激活 蛋白质-1(XBP-1s)，以支持它们的生长和生存。我们已经开发出一种名为B-I09的药物，它可以 有效抑制XBP-1，杀伤CLL细胞。此外，我们的新结果表明，CLL细胞 显著降低他们一种名为干扰素基因刺激物(STING)的蛋白质的表达。基于我们的 结果提示，减少CLL细胞的刺痛可能有助于其存活，我们建议使用Adu。 S100，一种目前处于临床试验中的刺激剂，刺激剩余的刺激物杀死CLL细胞。基于 XBP-1和STING在调节相同的生存机制即B细胞受体中的联系 (BCR)信号转导，我们建议测试B-I09和Adu-S100是否可以协同作用杀死培养的小鼠和 人CLL细胞。为了能够进行这些研究，我们设计了一种新的小鼠模型，在该模型中，CLL细胞 不会产生刺痛。我们将利用这个模型来测试ADU-S100是否可以激活免疫系统来 与B-I09协同有效根除慢性淋巴细胞性白血病。最后，基于我们最近在成功地 开发IRE-1/XBP-1通路的刺激反应抑制剂，我们建议将B-I09与A 高效表达的完整膜蛋白--人CD20的单域抗体(或纳米体) 在CLL细胞中的水平，以便将药物靶向这些细胞。由此产生的纳米体-药物结合物(NDC)将 在细胞和体内评价对XBP-1s的抑制，减轻肿瘤负荷，并与Adu-1协同作用 S100在一种新型的刺痛缺陷的、表达人CD20的CLL小鼠模型中。这些研究将作为 启动I期临床试验以治疗被诊断为CLL、DLBCL或潜在的人类患者的基础 使用XBP-1S抑制剂和刺激剂联合治疗的其他实体肿瘤。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-1能够被细胞特异性抑制- 1在不同类型的细胞中，只要这些细胞表达唯一的细胞表面标记。这些新奇的XBP-1S- 靶向NDCs也可用于询问各种细胞类型中IRE-1/XBP-1通路的生物学， 也可以作为治疗学。

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.