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，每年折磨15，000名新的美国人。患者通常在诊断后3.5年死亡，经历骨质破坏，导致脊柱畸形和疼痛。尽管恶性克隆发生了转化，但它通常依赖于其环境中的生长因子，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进展。Trk受体酪氨酸激酶及其神经营养因子配体由MM细胞表达，产生促进MM细胞系和原代MM细胞体外存活的信号传导环。使用可溶性Trk-Fc诱饵受体阻断Trk信号传导抑制异种移植模型中的MM生长。骨髓基质、内皮细胞、成骨细胞也表达神经营养蛋白，从而有助于在其有利的环境中支持MM。这些观察结果表明MM肿瘤进展中的神经营养因子-Trk轴，并导致cep 701作为抗MM治疗的临床前评价。Cep 701是吲哚咔唑K252 a的衍生物，对Trk和Jak 2的IC 50为3 nM。它特异性杀死培养物中的原代MM细胞和MM细胞系，并抑制植入NOD-SCID小鼠皮下组织的MM细胞系的生长。靶向Trk和Jak 2的能力可能是其强效抗MM活性的基础。本研究将评估Trk信号传导在MM疾病进展中的作用。具体而言，我们将：1）通过评估单独破坏Trk活化和与Jak 2抑制组合后的细胞活力，确定神经营养因子：Trk信号传导对MM肿瘤存活的重要性。2)描绘对神经营养蛋白的促存活作用至关重要的信号级联：MM中的Trk活化。3）鉴定MM中Trk和神经营养蛋白表达的普遍性，并将该表达与疾病特征（包括阶段、先前治疗、免疫球蛋白同种型和细胞遗传学）相关联。4）确定使用cep 701的双重Trk/Jak 2靶向是否将控制MM的SCID-hu模型中的MM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.