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Targeting CD44-mediated calcium signaling for the treatment of relapsed myeloma

靶向 CD44 介导的钙信号传导治疗复发性骨髓瘤

基本信息

批准号：
9135272
负责人：
Lori A Hazlehurst
金额：
$ 33.35万
依托单位：
WEST VIRGINIA UNIVERSITY
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：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135272
关键词：
Address Affect Agonist Binding Biochemical Biological Assay Biological Markers Bortezomib CD44 gene Calcium Calcium Channel Calcium Signaling Calcium ion Cell Death Cell Survival Cell membrane Cells Clinical Clinical Trials Coin Combined Modality Therapy Cyclic Peptides Disease Disulfides Dose Endoplasmic Reticulum Equilibrium Extracellular Matrix Gene Expression Genetic Goals Health Homeostasis Housing Hyaluronic Acid Ligands Maintenance Malignant Neoplasms Maximum Tolerated Dose Mediating Microfluidics Modeling Molecular Profiling Monoclonal gammopathy of uncertain significance Multiple Myeloma Necrosis New Agents Newly Diagnosed Oxidoreductase Patients Proteasome Inhibitor Quality of life Refractory Refractory Disease Regimen Regulation Relapse Research Resistance Role STIM1 gene Sampling Schedule Signal Pathway Signal Transduction Specimen Sulfhydryl Compounds Technology Testing Therapeutic Therapeutic Agents Tumorigenicity cell growth cohort design disulfide bond drug sensitivity endoplasmic reticulum stress genetic approach in vitro Model in vivo in vivo Model innovation knock-down mathematical model multicatalytic endopeptidase complex novel novel therapeutics pre-clinical preclinical study relapse patients response sensor small molecule standard of care treatment response tumor microenvironment validation studies

项目摘要

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is a malignancy that initially responds to standard of care agents. Unfortunately, however, all patients relapse with disease that is refractory to further treatment. We hypothesize that progression and maintenance of MM requires balanced CD44 signaling that controls homeostasis of intracellular Ca2+ pools, as we have shown that a first in class, in-house small molecule selective agonist of CD44 coined MTI-101 provokes toxic increases in the levels of intracellular Ca2+ that trigger MM cell necrosis. Further, we have identified key effectors downstream of CD44 that appear to control intracellular Ca2+ levels and to contribute to MTI-101-induced necrotic cell death, specifically an endoplasmic reticulum (ER) resident thiol oxidoreductase coined Ero1L and its target Stim1, an ER/plasma membrane (single-pass) calcium sensor. Importantly, we have also shown that: (i) MTI-101 has activity against both primary and relapsed multiple myeloma; (ii) Ero1L expression in MM patient samples correlates with sensitivity to MTI-101; and (iii) knockdown of Ero1L augments the sensitivity of MM to bortezomib-induced cell death. In Specific Aim 1 we will fully interrogate the status of the CD44-Ero1L-Stim1-Ca2+ circuit in primary myeloma specimens (MGUS, newly diagnosed and proteasome inhibitor refractory disease) and will assess effects of CD44 engagement by MTI-101 versus its natural ligand hyaluronic acid (HA) on intracellular Ca2+ levels and MM cell survival. We will also evaluate if levels of Ero1L and Stim1 in primary and relapsed MM correlate with sensitivity to MTI-101, with changes in intracellular Ca2+ pools following CD44 engagement, and with clinical resistance to bortezomib treatment. In Specific Aim 2 genetic and biochemical approaches will be used to assess the regulation and roles of Ero1L and Stim1 in the response to MTI-101 versus HA, and their roles in MTI-101 and bortezomib efficacy as therapeutics for myeloma in vivo. Finally, in Specific Aim 3 we will use mathematical models and validation studies to optimize single agent and combination therapy with MTI-101. We submit the proposed studies will establish the mechanism of action and efficacy of this exciting new agent that targets CD44-Ero1L- Stim1-Ca2+ circuit in both primary and relapsed multiple myeloma.

描述（由申请人提供）：多发性骨髓瘤 (MM) 是一种最初对标准护理药物有反应的恶性肿瘤。然而不幸的是，所有患者都会因进一步治疗难以治愈的疾病而复发。我们假设 MM 的进展和维持需要平衡的 CD44 信号传导来控制细胞内 Ca2+ 池的稳态，因为我们已经证明，首创的内部 CD44 小分子选择性激动剂 MTI-101 会引起细胞内 Ca2+ 水平的毒性增加，从而引发 MM 细胞坏死。此外，我们还确定了 CD44 下游的关键效应子，这些效应子似乎控制细胞内 Ca2+ 水平并有助于 MTI-101 诱导的坏死性细胞死亡，特别是内质网 (ER) 驻留硫醇氧化还原酶 (Ero1L) 及其靶标 Stim1（一种 ER/质膜（单程）钙传感器）。重要的是，我们还表明：（i）MTI-101 具有抗原发性和复发性多发性骨髓瘤的活性； (ii) MM 患者样本中的 Ero1L 表达与 MTI-101 的敏感性相关； (iii) Ero1L 的敲除增强了 MM 对硼替佐米诱导的细胞死亡的敏感性。在具体目标 1 中，我们将全面探究原发性骨髓瘤标本（MGUS、新诊断的蛋白酶体抑制剂难治性疾病）中 CD44-Ero1L-Stim1-Ca2+ 回路的状态，并将评估 MTI-101 与其天然配体透明质酸 (HA) 结合 CD44 对细胞内 Ca2+ 水平和 MM 细胞存活的影响。我们还将评估原发性和复发性 MM 中的 Ero1L 和 Stim1 水平是否与对 MTI-101 的敏感性、CD44 参与后细胞内 Ca2+ 池的变化以及对硼替佐米治疗的临床耐药性相关。在特定目标 2 中，将使用遗传和生化方法来评估 Ero1L 和 Stim1 在 MTI-101 与 HA 反应中的调节和作用，以及它们在 MTI-101 和硼替佐米作为体内骨髓瘤治疗药物的疗效中的作用。最后，在具体目标 3 中，我们将使用数学模型和验证研究来优化 MTI-101 的单药和联合治疗。我们提出的研究将建立这种令人兴奋的新药物的作用机制和功效，该新药物针对原发性和复发性多发性骨髓瘤中的 CD44-Ero1L-Stim1-Ca2+ 回路。