Neurotrophin Signaling in Multiple Myeloma

描述（由申请人提供）：多发性骨髓瘤（MM）是一种无法治愈的恶性肿瘤，每年有15,000名美国新患者遭受折磨。患者通常在确诊后3.5年死亡，经历骨破坏导致脊柱畸形和疼痛。尽管它发生了转化，但恶性克隆往往依赖于其环境中的生长因子，而不是为了生长——MM是一种缓慢增殖的疾病——而是为了生存。本研究的目的是严格检验神经营养因子信号传导有助于这些生存信号的假设，以及神经营养因子信号传导的抑制将控制MM的进展。Trk受体酪氨酸激酶及其神经营养因子配体在MM细胞中表达，形成一个信号环，促进MM细胞系和原代MM细胞的体外存活。在异种移植物模型中，使用可溶性Trk- fc诱饵受体阻断Trk信号传导抑制MM生长。骨髓基质、内皮细胞和成骨细胞也表达神经营养因子，因此有助于支持MM在其有利的环境中生长。这些观察结果表明神经营养因子- trk轴在MM肿瘤进展中起作用，并导致cep701作为抗MM治疗的临床前评估。Cep701是吲哚咔唑K252a的衍生物，对Trk和Jak2的IC50为3 nM。特异性杀伤原代MM细胞和培养MM细胞系，抑制植入NOD-SCID小鼠皮下组织的MM细胞系生长。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MM疾病进展中的作用。具体而言，我们将：1)通过单独破坏Trk激活和联合Jak2抑制后评估细胞活力，确定神经营养因子：Trk信号传导对MM肿瘤存活的重要性。2)描述神经营养因子：Trk在MM中的激活对促生存作用至关重要的信号级联。3)确定Trk和神经营养因子在MM中的表达，并将这种表达与疾病特征（包括分期、既往治疗、免疫球蛋白同型和细胞遗传学）联系起来。4)在MM的SCID-hu模型中，确定使用cep701靶向Trk/Jak2是否能控制MM疾病的进展。

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.