Pharmacological Blockage of XBP-1s Expression in Cancer

XBP-1s 在癌症中表达的药理学阻断

• 批准号: 9985524
• 负责人: Juan R Del Valle
• 金额: $ 46.5万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-14 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9985524
• 关键词: ATF6 gene; Acute Lymphocytic Leukemia; Aldehydes; Antineoplastic Agents; Apoptosis; B lymphoid malignancy; B-Cell Leukemia; 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; Emu species; 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; chronic lymphocytic leukemia cell; 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

 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(申请人提供)：恶性细胞的高增殖率通常与蛋白质折叠、组装和运输的速度增加有关。恶劣的肿瘤微环境也促进了内质网应激反应的过度激活，这是一种重要的生存机制。内质网应激反应在成熟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了，因为白血病和淋巴瘤细胞不像多发性骨髓瘤细胞那样扩大其内质网。然而，我们的研究表明，慢性淋巴细胞白血病(CLL)确实需要激活内质网应激反应途径才能生存。IRE-1/XBP-1通路是最保守的内质网应激反应通路。IRE-1含有一个管腔应力敏感结构域和一个胞浆激酶/核糖核酸酶结构域。RNase结构域对IRE-1的功能至关重要，因为它从XBP-1mRNA中拼接26个核苷酸，导致翻译中的框架移位。剪接的XBP-1mRNA编码一个54 kDa的XBP-1S转录因子，该转录因子移位到细胞核并诱导伴侣和脂类的表达，以帮助蛋白质折叠和运输。虽然大多数转录因子仍然无法用药，但XBP-1的特殊激活机制使IRE-1成为治疗干预的一个有吸引力的靶点。我们最近开发了一种结构新颖的IRE-1抑制剂B-I09，并证明了它能够在完整细胞中阻断XBP-1的表达，并在体内减少CLL肿瘤负担。对IRE-1/XBP-1通路的遗传和药物抑制会损害BCR信号，而B-I09与BTK抑制剂ibrutinib协同抑制原代小鼠和人B细胞癌细胞的生长。该项目寻求利用B-I09和具有改进的药代动力学特性的精选前药类似物与bcr信号抑制物结合用于治疗B细胞癌。我们实施了一种综合的方法，包括机械细胞生物学、体内疗效研究和化学优化，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B-I09与bcr信号通路抑制剂伊布鲁替尼(批准的套细胞淋巴瘤)和福斯塔替尼(II期淋巴瘤)在B细胞癌细胞系、原代小鼠CLL细胞、原代人类样本以及活体Eµ-TLC1小鼠CLL模型中的作用机制和协同作用。在目标2中，我们将优化XBP-1s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类新型抗癌药物的生物利用度，用于高级临床前研究。