Myeloma stem cell targeting by liver x receptors

肝脏 x 受体靶向骨髓瘤干细胞

基本信息

批准号：
8189635
负责人：
WILLIAM H MATSUI
金额：
$ 22.31万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189635
关键词：
Affect Agonist Animals Antineoplastic Agents Attenuated B-Lymphocytes Bone Marrow Cell physiology Cells Characteristics Cholesterol Clinical Clonal Expansion Data Disease Drug resistance Embryonic Development Erinaceidae Exhibits Frequencies Growth Human Immunodeficient Mouse Immunoglobulin Gene Rearrangement In Vitro Inflammatory Ligands Liver Malignant - descriptor Malignant Neoplasms Mediating Memory B-Lymphocyte Multiple Myeloma Mutation Normal Cell Nuclear Hormone Receptors Outcome Pathway interactions Plasma Cells Production Property Recurrent disease Relapse Reporting Resistance Role Signal Transduction Pathway Solid Neoplasm Specimen Stem cells Stromal Cells Symptoms Therapeutic Transplantation cancer stem cell chemotherapeutic agent design hedgehog signal transduction improved in vivo inhibitor/antagonist neoplastic cell novel novel strategies plasma cell differentiation receptor research clinical testing resistance mechanism self-renewal smoothened signaling pathway therapeutic target tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Although mature plasma cells constitute the vast majority of tumor cells and are responsible for clinical symptoms in multiple myeloma (MM), they have little to no clonogenic growth potential either in vitro or in vivo. We have recently found that clonotypic MM cells phenotypically resembling normal memory B cells are able to give rise to mature plasma cells in immunodeficient mice and propagate disease during serial transplantation. These results demonstrate that these cells are capable of both differentiation and self-renewal, suggesting that they represent the cancer stem cell (CSC) in MM. We have recently found that MM CSCs are resistant to standard chemotherapeutic agents, but can be targeted by the Hedgehog (Hh) signaling pathway that is active during normal embryonic development and in a wide variety of cancers. Several novel Hh pathway inhibitors have recently entered clinical testing, and one of these has exhibited clinical activity validating Hh signaling as a therapeutic target in human cancers. However, all of these approaches have been designed to inhibit SMOOTHEDED (SMO) a key component of the Hh signal transduction pathway, and emergence of resistance mechanisms have been reported. Therefore, novel strategies capable of inhibiting Hh signaling without directly targeting SMO are needed. Our preliminary data demonstrate that agonists of the Liver X Receptor (LXR), a nuclear hormone receptor that interacts with Hh signaling in normal cells, can attenuate Hh pathway activity in MM, reduce the frequency of MM CSC, and limit clonogenic MM growth in vitro. Therefore, we hypothesize that LXR agonists are novel anti-cancer agents that may target MM CSCs through the inhibition of Hh signaling. We propose to build on these findings and will specifically: 1). Examine the effects of LXR agonists in MM and 2). Examine the interaction between the LXR and Hedgehog signaling pathways in MM. PUBLIC HEALTH RELEVANCE: Multiple myeloma is largely an incurable disease, but we recently identified myeloma stem cells that may be responsible for disease relapse and progression. We will study whether a novel pathway regulated by the Liver X receptor can inhibit myeloma stem cells and improve clinical outcomes.

描述（由申请人提供）：尽管成熟浆细胞构成了肿瘤细胞的绝大多数并且是多发性骨髓瘤（MM）临床症状的原因，但它们在体外或体内几乎没有克隆生长潜力。我们最近发现，表型类似于正常记忆 B 细胞的克隆型 MM 细胞能够在免疫缺陷小鼠体内产生成熟浆细胞，并在连续移植过程中传播疾病。这些结果表明这些细胞能够分化和自我更新，表明它们代表 MM 中的癌症干细胞 (CSC)。我们最近发现 MM CSC 对标准化疗药物具有耐药性，但可以被 Hedgehog (Hh) 信号通路靶向，该通路在正常胚胎发育和多种癌症中都很活跃。几种新型 Hh 通路抑制剂最近已进入临床测试，其中一种已表现出临床活性，验证了 Hh 信号传导作为人类癌症的治疗靶点。然而，所有这些方法都旨在抑制 Hh 信号转导途径的关键组成部分 SMOOTHEDED (SMO)，并且已报道出现耐药机制。因此，需要能够抑制 Hh 信号传导而不直接靶向 SMO 的新策略。我们的初步数据表明，肝脏 X 受体 (LXR)（一种与正常细胞中 Hh 信号传导相互作用的核激素受体）的激动剂可以减弱 MM 中的 Hh 通路活性，降低 MM CSC 的频率，并限制体外克隆性 MM 生长。因此，我们假设 LXR 激动剂是新型抗癌药物，可能通过抑制 Hh 信号传导来靶向 MM CSC。我们建议以这些发现为基础，并将具体：1)。检查 LXR 激动剂对 MM 和 2) 的影响。检查 MM 中 LXR 和 Hedgehog 信号通路之间的相互作用。公共卫生相关性：多发性骨髓瘤在很大程度上是一种无法治愈的疾病，但我们最近发现骨髓瘤干细胞可能导致疾病复发和进展。我们将研究由肝脏 X 受体调节的新途径是否可以抑制骨髓瘤干细胞并改善临床结果。