Retinoid Based Treatment Approaches to Target the Myeloma Stem Cell

基于类维生素A的靶向骨髓瘤干细胞的治疗方法

• 批准号: 7989502
• 负责人: FENGHUANG ZHAN
• 金额: $ 19.64万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989502
• 关键词: Aftercare; Animal Model; Apoptosis; B-Lymphocytes; Biological Process; Bortezomib; Cell Death; Cell Fraction; Cell Line; Cell Survival; Cells; Clinical; Combined Modality Therapy; Coxibs; Data; Databases; Disease; Drug Delivery Systems; Drug resistance; Erinaceidae; Genes; Genetic; Goals; Growth; In Vitro; Maintenance; Malignant Neoplasms; Mediating; Molecular; Multiple Myeloma; NOD/SCID mouse; Newly Diagnosed; Notch and Wnt Signaling Pathway; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Property; Protein Isoforms; Proteins; Radio; Recurrent disease; Reporting; Resistance; Retinoids; Role; SCID-hu Mice; Signal Pathway; Signal Transduction; Soft Agar Assay; Stem cells; Stream; Testing; Thalidomide; Time; Treatment Failure; Tretinoin; Tumorigenicity; Variant; Work; base; cancer stem cell; cell growth; efficacy testing; in vivo; in vivo Model; inhibitor/antagonist; killings; mouse model; neoplastic cell; novel strategies; novel therapeutic intervention; overexpression; public health relevance; receptor; self-renewal; stem cell niche; stemness

DESCRIPTION (provided by applicant): Multiple myeloma (MM) remains largely an incurable disease. The persistence of a drug-resistant cell population, probably the MM stem cells may be the cause of disease relapse. CD138-negative (CD138-) MM cell fraction was reported to contain MM stem cells. However, little is known about the molecular base of MM stem cells, which makes it difficult to specifically target these cells. Our preliminary data show that RAR1 is the top one up-regulated gene in CD138- MM stem cells compared to CD138+ tumor cells. RAR1 has two major isoforms, RAR11 and RAR12. Real-time PCR further demonstrated that it was RAR12 but not RAR11 that increased in CD138- MM stem cells. While RAR11 was ubiquitously expressed in MM cells, RAR12 was present in MM cells from about 30% of newly diagnosed patients. Patients with RAR12 expression had shorter overall-survival. RAR12-knockdown in RAR12+ MM cells induced cell growth arrest and apoptosis. Interestingly, ATRA selectively killed RAR12-overexpressing CD138- MM stem cells while sparing CD138+ tumor cells. Forced expression of RAR12 in RAR12-deficient MM tumor cells restored sensitivity to ATRA. We also found that Wnt signaling is activated in CD138- MM stem cells and ATRA down-regulates Wnt signaling. Our hypothesis is that RAR12 maintains the "stemness" and drug-resistance of MM stem cells by activating the Wnt/2-catenin pathway; and ATRA and other retinoids work through interference with Wnt signaling, which leads to loss of "stemness" features. The goal of this work is to determine the mechanisms by which RAR12 maintains the "stemness" features of MM stem cells and how retinoids kill MM stem cells. In specific Aim 1, we will evaluate the expression levels of RARa2 in primary MM stem cells and to test RARa2 functions in maintenance of MM stemness in animal models. In specific Aim 2, we will determine functional roles of Wnt signaling pathway in the ATRA/RARa2-induced MM stem cell apoptosis. Finally, in specific Aim 3, we will exploit new approaches based on retinoid agents and drugs targeting Wnt pathway for the therapy of MM stem cells and MM disease in SCID-hu mice. Our proposed study may provide better understanding of the biological functions of RAR12 in MM stem cells and is likely to add valuable information on new therapeutic approaches for MM stem cells which may significantly impact the clinical outcome of MM diseases. Since cancer stem cells exist in variant cancer malignancies, the proposed study may also have a major impact on the treatment of other cancers. PUBLIC HEALTH RELEVANCE: Project Narrative Cancer stem cells are identified in an increasing list of malignancies, including multiple myeloma, and are thought to be responsible for treatment failure and re-growth of cancers after treatment. However, the mechanisms by which cancer stem cells maintain their "stemness" features are still poorly understood. We have identified a protein in myeloma stem cells that may be responsible for stem cell growth and survival and may also play a crucial role in retinoid-based therapy in myeloma disease.

描述（由申请人提供）：多发性骨髓瘤（MM）在很大程度上仍然是一种无法治愈的疾病。耐药细胞群的持久性，可能是MM干细胞可能是疾病复发的原因。据报道，CD138阴性（CD138-）MM细胞馏分包含MM干细胞。然而，对MM干细胞的分子碱很少了解，这使得很难具体靶向这些细胞。我们的初步数据表明，与CD138+肿瘤细胞相比，RAR1是CD138-MM干细胞中最高的上调基因。 RAR1具有两个主要的同工型RAR11和RAR12。实时PCR进一步表明，在CD138-mM干细胞中增加的是RAR12，但不是RAR11。虽然RAR11在MM细胞中普遍表达，但RAR12存在于大约30％的新诊断患者的MM细胞中。 RAR12表达的患者的整体生存时间较短。 RAR12+ MM细胞中的RAR12-敲低诱导细胞生长停滞和凋亡。有趣的是，在放大CD138+肿瘤细胞的同时，ATRA选择性地杀死了反射过表达的CD138-MM干细胞。 RAR12在RAR12缺陷型MM肿瘤细胞中的强迫表达恢复了对ATRA的敏感性。我们还发现，Wnt信号在CD138-MM干细胞中激活，并且ATRA下调WNT信号传导。我们的假设是RAR12通过激活Wnt/2-catenin途径来维持MM干细胞的“干性”和抗药性。 ATRA和其他类维生素类动物通过干扰Wnt信号传导起作用，这导致了“茎”特征的丧失。这项工作的目的是确定RAR12保持MM干细胞的“干性”特征以及类维生素类似如何杀死MM干细胞的机制。在特定目标1中，我们将评估原代MM干细胞中RARA2的表达水平，并测试RARA2在动物模型中MM干性维持中的功能。在特定的目标2中，我们将确定Wnt信号通路在ATRA/RARA2诱导的MM干细胞凋亡中的功能作用。最后，在特定的目标3中，我们将基于靶向WNT途径的类维生素类药物和药物来利用新方法，以治疗SCID-HU小鼠的MM干细胞和MM疾病。我们提出的研究可能会更好地了解MM干细胞中RAR12的生物学功能，并且很可能会在MM干细胞的新治疗方法上添加有价值的信息，这可能会严重影响MM疾病的临床结果。由于癌症干细胞存在于变异性癌症恶性肿瘤中，因此拟议的研究也可能对其他癌症的治疗产生重大影响。 公共卫生相关性： 在包括多发性骨髓瘤在内的越来越多的恶性肿瘤清单中鉴定出项目叙事癌干细胞，并被认为是治疗后的治疗失败和癌症的重长。但是，癌症干细胞保持其“干性”特征的机制仍然很少了解。我们已经确定了可能导致干细胞生长和生存的骨髓瘤干细胞中的蛋白质，并且在基于视黄素的骨髓瘤疗法中也可能起着至关重要的作用。