Pharmacological Blockage of XBP-1s Expression in Cancer

XBP-1s 在癌症中表达的药理学阻断

基本信息

批准号：
9331586
负责人：
Juan R Del Valle
金额：
$ 45.36万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-14 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9331586
关键词：
ATF6 gene Acute Lymphocytic Leukemia Aldehydes Antineoplastic Agents Apoptosis B lymphoid malignancy B-Lymphocytes BCR Signaling Pathway Back Binding Proteins Biological Availability Cancer cell line Cell Differentiation process Cell Line Cell Nucleus Cell Survival Cell physiology Cells Cellular biology Chemicals Chronic Lymphocytic Leukemia Clinic Coin Development Drug Combinations Drug Kinetics Endoplasmic Reticulum Equilibrium Exhibits FDA approved Gene Dosage Genes Genetic Growth Human In Vitro Intervention Knock-out Knockout Mice Lead Lipids Lymphoma Maintenance Malignant - descriptor Malignant Neoplasms Mantle Cell Lymphoma Masks Mature B-Lymphocyte Mediating Messenger RNA Modeling Molecular Chaperones Multiple Myeloma Mus Mutagenesis Nucleotides Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacology Phase Phenols Phosphotransferases Plasma Prodrugs Property Proteins Proteomics RNA Splicing Reporting Research Ribonucleases Role Safety Sampling Series Signal Pathway Signal Transduction Solubility Stress Structure Testing Therapeutic Intervention Transgenic Organisms Translations Tumor Burden acute toxicity analog base biological adaptation to stress cancer cell cell growth efficacy study endoplasmic reticulum stress functional group improved in vivo inhibitor/antagonist knock-down leukemia leukemia/lymphoma malignant breast neoplasm mouse model neoplastic cell non-oncogenic novel novel therapeutics preclinical study protein expression protein folding protein transport proteotoxicity public health relevance response sensor small molecule synergism systemic toxicity targeted treatment transcription factor treatment strategy tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The high proliferation rate of malignant cells is often associated with an increase in the rates of protein folding, assembly, and transport. The harsh tumor microenvironment also contributes to hyperactivation of the endoplasmic reticulum (ER) stress response as an important survival mechanism. The functional role of the ER stress response in mature B-cell leukemia or lymphoma has been largely overlooked because leukemia and lymphoma cells do not expand their ER like that of multiple myeloma cells. However, our studies have shown that chronic lymphocytic leukemia (CLL) indeed requires activation of the ER stress response pathway for survival. The IRE-1/XBP-1 pathway represents the most conserved ER stress response pathway. IRE-1 contains a luminal stress-sensor domain, and a cytoplasmic kinase/RNase domain. The RNase domain is critical for the function of IRE-1, because it splices 26 nucleotides from the XBP-1 mRNA, causing a frame shift in translation. The spliced XBP-1 mRNA encodes a functional 54-kDa XBP-1s transcription factor, which translocates to the nucleus and induces the expression of chaperones and lipids to aid in protein folding and trafficking. While most transcription factors remain undruggable, the specific activation mechanism of XBP-1 renders IRE-1 an attractive target for therapeutic intervention. We recently developed a structurally novel IRE-1 inhibitor, B-I09, and demonstrated its ability to block XBP- 1 expression in intact cells and to reduce CLL tumor burden in vivo. Genetic and pharmacological inhibition of the IRE-1/XBP-1 pathway compromises BCR signaling, and B-I09 synergizes with the BTK inhibitor ibrutinib to inhibit the growth of primary mouse and human B-cell cancer cells. This project seeks to utilize B-I09 and selected prodrug analogs with improved pharmacokinetic properties in combination with inhibitors of BCR signaling for the treatment of B-cell cancer. We have implemented an integrated approach encompassing mechanistic cell biology, in vivo efficacy studies, and chemical optimization to develop novel treatment strategies for CLL and other B-cell malignancies. In Aim 1, we proposed to evaluate the mechanism of action and synergy of B-I09 in combination with the BCR signaling pathway inhibitors ibrutinib (approved, mantle cell lymphoma, CLL) and fostamatinib (phase II, lymphoma) in B-cell cancer cell lines, primary mouse CLL cells, primary human samples, and in an in vivo Eµ-TLC1 mouse model of CLL. In Aim 2, we will optimize the pharmacokinetic properties of inhibitors of XBP-1s expression and employ novel prodrug strategies to improve the bioavailability of this new class of anticancer agents for advanced preclinical studies.

描述（由申请人提供）：恶性细胞的高增殖率通常与蛋白质折叠、组装和运输速率的增加相关，恶劣的肿瘤微环境也导致内质网（ER）应激反应的过度激活。 ER应激反应在成熟B细胞白血病或淋巴瘤中的功能作用在很大程度上被忽视，因为白血病和淋巴瘤细胞不像多发性骨髓瘤那样扩大其ER。然而，我们的研究表明，慢性淋巴细胞白血病 (CLL) 确实需要激活 ER 应激反应途径才能生存。 IRE-1/XBP-1 途径代表了最保守的 IRE-1 反应途径。 RNase 结构域对于 IRE-1 的功能至关重要，因为它剪接 XBP-1 mRNA 的 26 个核苷酸，从而产生应激反应。剪接的 XBP-1 mRNA 编码功能性 54-kDa XBP-1s 转录因子，它易位到细胞核并诱导伴侣和脂质的表达，以帮助蛋白质折叠和运输。由于 XBP-1 的特异性激活机制使 IRE-1 成为治疗干预的有吸引力的靶标，我们最近开发了一种结构新颖的 IRE-1 抑制剂 B-I09，并证明了其能力。阻断完整细胞中的 XBP-1 表达并减少体内 CLL 肿瘤负荷，IRE-1/XBP-1 通路的遗传和药理学抑制会损害 BCR 信号传导，并且 B-I09 与 BTK 抑制剂依鲁替尼协同作用以抑制生长。该项目旨在利用 B-I09 和选定的具有改善的药代动力学特性的前药类似物与 BCR 信号传导抑制剂相结合来治疗B 细胞癌症。我们实施了一种涵盖机械细胞生物学、体内功效研究和化学优化的综合方法，以开发针对 CLL 和其他 B 细胞恶性肿瘤的新治疗策略。在目标 1 中，我们建议评估作用机制。 B-I09 与 BCR 信号通路抑制剂 ibrutinib（已批准，套细胞淋巴瘤，CLL）和 fostamatinib（II 期，淋巴瘤）联合在 B 细胞癌细胞系、原代小鼠中的协同作用CLL 细胞、原代人类样本和 CLL 体内 Eμ-TLC1 小鼠模型在目标 2 中，我们将优化 XBP-1 表达抑制剂的药代动力学特性，并采用新的前药策略来提高这一新类别的生物利用度。用于高级临床前研究的抗癌药物。