Neurotrophin Signaling in Multiple Myeloma

多发性骨髓瘤中的神经营养蛋白信号转导

基本信息

批准号：
7653631
负责人：
ROGER N PEARSE
金额：
$ 23.16万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7653631
关键词：
Adhesions American Antibodies Autocrine Communication Bone Marrow Brain-Derived Neurotrophic Factor CEP 701 Cell Line Cell Survival Cells Cytogenetics Data Deformity Diagnosis Disease Disease Marker Disease Progression Endothelial Cells Environment Fc Receptor Growth Growth Factor Human Immunoblotting Immunoglobulin Isotypes Implant In Vitro Inhibitory Concentration 50 K 252a Learning Ligands MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Maps Modeling Multiple Myeloma Mus NOD/SCID mouse Nervous system structure Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Neurotrophin 3 Osteoblasts Pain Pathogenesis Pathway interactions Patients Phosphorylation Phosphotyrosine Plasma Prevalence Prior Therapy Proliferating Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Research Personnel Role Signal Transduction Small Interfering RNA Staging Subcutaneous Tissue System Testing Therapeutic Vertebral column Xenograft Model autocrine bone disease characteristic experience inhibitor/antagonist killings kinase inhibitor migration neoplastic cell neurotrophic factor paracrine preclinical evaluation programs receptor response small molecule therapeutic target tumor tumor progression

项目摘要

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.

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，每年困扰 15,000 名新美国人。患者通常在诊断后 3.5 年死亡，骨质破坏导致脊柱畸形和疼痛。尽管发生了转化，恶性克隆通常依赖于其环境中的生长因子，不是为了生长（多发性骨髓瘤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蛋白信号传导对这些生存信号有贡献以及抑制神经营养蛋白信号传导将控制 MM 进展的假设。 Trk 受体酪氨酸激酶及其神经营养蛋白配体由 MM 细胞表达，形成信号环路，促进 MM 细胞系和原代 MM 细胞在体外的存活。使用可溶性 Trk-Fc 诱饵受体阻断 Trk 信号传导可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素，因此有助于在其有利的环境中支持多发性骨髓瘤。这些观察结果表明 MM 肿瘤进展中存在神经营养蛋白-Trk 轴，并导致 cep701 作为抗 MM 疗法的临床前评估。 Cep701 是吲哚咔唑 K252a 的衍生物，对于 Trk 和 Jak2 的 IC50 为 3 nM。它特异性杀死原代 MM 细胞和培养中的 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。同时靶向 Trk 和 Jak2 的能力可能是其有效的抗 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。具体来说，我们将： 1) 通过单独破坏 Trk 激活以及与 Jak2 抑制相结合后评估细胞活力，确定神经营养蛋白：Trk 信号转导对 MM 肿瘤存活的重要性。 2) 描述对多发性骨髓瘤中神经营养蛋白：Trk 激活的促生存作用至关重要的信号级联。 3) 确定 MM 中 Trk 和神经营养蛋白表达的流行率，并将这种表达与疾病特征（包括分期、既往治疗、免疫球蛋白同种型和细胞遗传学）相关联，4) 确定使用 cep701 的双重 Trk/Jak2 靶向是否会控制 MM 疾病进展MM的SCID-hu模型。