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: 10462813
• 负责人: Juan R Del Valle
• 金额: $ 58.99万
• 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/10462813
• 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; DNA; Data; Development; Diagnosis; Disease; Drug Targeting; Drug resistance; Elderly; Engineering; Exhibits; FDA approved; Foundations; Gene Activation; Genes; Growth; Head and Neck Neoplasms; Hematopoietic Neoplasms; Human; Human body; Immune system; Immunity; Immunization; In Vitro; Indolent; Infection; Integral Membrane Protein; Interferon Type I; Lead; 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; XBP1 gene; anti-tumor immune response; base; biological adaptation to stress; cancer cell; cancer therapy; cancer type; cell type; chronic lymphocytic leukemia cell; combat; combinatorial; endoplasmic reticulum stress; in vivo; indexing; inhibitor; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; mouse model; nanobodies; novel; novel therapeutic intervention; pembrolizumab; sortase; synergism; treatment strategy

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.

项目总结