Neurotrophin Signaling in Multiple Myeloma

描述(申请人提供)：多发性骨髓瘤(MM)是一种无法治愈的恶性肿瘤，每年折磨着15,000名新的美国人。患者通常在确诊后3.5年内死亡，经历骨骼破坏导致脊柱变形和疼痛。尽管发生了转化，但恶性克隆往往依赖于环境中的生长因素，而不是生长--多发性骨髓瘤是一种缓慢扩散的疾病--而是为了生存。这项研究的目的是对神经营养因子信号有助于这些生存信号以及抑制神经营养因子信号将控制多发性骨髓瘤进展的假设进行批判性检验。多发性骨髓瘤细胞表达TrK受体酪氨酸激酶及其神经营养因子配体，形成一个信号环，促进体外培养的多发性骨髓瘤细胞株和原代多发性骨髓细胞的存活。在异种移植模型中，使用可溶性Trk-Fc诱骗受体阻断Trk信号可抑制MM的生长。神经营养因子也在骨髓基质、内皮细胞、成骨细胞中表达，因此有助于MM在其有利的环境中的支持。这些观察提示神经营养素-Trk轴在多发性骨髓瘤的进展中，并导致了临床前对CEP701作为抗多发性骨髓瘤治疗的评估。Cep701是吲哚咔唑K252a的衍生物，对Trk和JAK2的IC50为3 nM。它对原代培养的MM细胞和培养的MM细胞系均有特异性杀伤作用，并抑制移植到NOD-SCID小鼠皮下组织中的MM细胞系的生长。靶向Trk和JAK2的能力可能是其强大的抗MM活性的基础。本研究将评估Trk信号在多发性骨髓瘤疾病进展中的作用。具体地说，我们将：1)通过单独干扰Trk激活和联合JAK2抑制后评估细胞活力，确定神经营养素：Trk信号对MM肿瘤生存的重要性。2)阐明神经营养素促生存效应的关键信号通路：MM中Trk的激活。3)鉴定MM中Trk和神经营养素的表达情况，并将其表达与疾病特征包括分期、既往治疗、免疫球蛋白同型和细胞遗传学相关联，4)确定在MM的SCID-Hu模型中，使用CEP701靶向Trk/JAK2是否可以控制MM的疾病进展。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable malignancy that afflicts 15,000 new Americans each year. Patients typically die 3.5 years after diagnosis, experiencing bone destruction leading to spine deformities and pain. Despite its transformation, the malignant clone is often dependent on growth factors in its environment, not for growth - MM is a slowly proliferating disease - but for survival. The objective of this study is to critically test the hypotheses that neurotrophin signaling contributes to these survival signals, and that inhibition of neurotrophin signaling will control MM progression. Trk receptor tyrosine kinases and their neurotrophin ligands are expressed by MM cells, creating a signaling loop that promotes the survival of MM cell lines and primary MM cells in vitro. Blockade of Trk signaling, using a soluble Trk-Fc decoy receptor, inhibits MM growth in a xenograft model. Neurotrophins are also expressed by bone marrow stroma, by endothelial cells, by osteoblasts, and thus contribute to the support of MM within its favored environment. These observations suggest a neurotrophin-Trk axis in MM tumor progression, and led to preclinical evaluation of cep701 as anti-MM therapy. Cep701 is a derivative of the indolcarbazole, K252a, with an IC50 of 3 nM for Trk and for Jak2. It specifically kills both primary MM cells and MM cell lines in culture, and inhibits growth of MM cell lines implanted into the subcutaneous tissue of NOD-SCID mice. The ability to target both Trk and Jak2 likely underlies its potent anti-MM activity. This study will evaluate the role of Trk signaling in MM disease progression. Specifically, we will: 1) Determine the importance of neurotrophin: Trk signaling to MM tumor survival, by assessing cell viability after disrupting Trk activation alone and in combination with Jak2 inhibition. 2) Delineate the signaling cascades that are critical to the pro-survival effects of neurotrophin:Trk activation in MM. 3) Identify the prevalence of Trk and neurotrophin expression by MM, and correlate this expression with disease characteristics including stage, prior therapies, immunoglobulin isotype, and cytogenetics, 4) Establish whether dual Trk/Jak2 targeting using cep701 will control MM disease progression in the SCID-hu model of MM.