Myeloma stem cell targeting by liver x receptors

描述（由申请方提供）：尽管成熟浆细胞构成了肿瘤细胞的绝大多数，并导致多发性骨髓瘤（MM）的临床症状，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，克隆型MM细胞的表型类似于正常的记忆B细胞能够在免疫缺陷小鼠中产生成熟的浆细胞，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抗性，但可以通过Hedgehog（Hh）信号通路靶向，该通路在正常胚胎发育期间和各种癌症中具有活性。几种新的Hh通路抑制剂最近已进入临床测试，其中一种已显示出临床活性，验证了Hh信号传导作为人类癌症的治疗靶点。然而，所有这些方法都被设计成抑制Hh信号转导途径的关键组分SMOOTHEDED（SMO），并且已经报道了抗性机制的出现。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，可通过抑制Hh信号传导靶向MM CSC。我们建议以这些发现为基础，具体如下：1）。检查LXR激动剂在MM和2）中的作用。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不治之症，但我们最近发现了可能导致疾病复发和进展的骨髓瘤干细胞。我们将研究由肝脏X受体调控的新途径是否可以抑制骨髓瘤干细胞并改善临床结果。

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.