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Validating the eCyPA/CD147 signaling complex for myeloma therapy

验证 eCyPA/CD147 信号复合物用于骨髓瘤治疗

基本信息

批准号：
9103033
负责人：
RUBEN D CARRASCO
金额：
$ 39.48万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9103033
关键词：
Apoptosis Area Aspirate substance BCL9 gene Binding Biological Assay Biopsy Bone Marrow Bone Marrow Cells CD14 gene Cell Communication Cell Survival Cells Chronic Lymphocytic Leukemia Complement-Dependent Cytotoxicity Complex Cyclophilin A Data Development Disease Disease Progression Disease Resistance Drug resistance Endothelial Cells Enzyme-Linked Immunosorbent Assay Future Genes Goals Growth Hematologic Neoplasms Home environment Immune Immunoblotting In Vitro Individual Light Malignant - descriptor Malignant Neoplasms Measures Mediating Medicine Modeling Multiple Myeloma Mus Natural History Neoplasms Non-Hodgkin&apos s Lymphoma Normal Cell Output Pathogenesis Patient-Focused Outcomes Patients Plasma Cells Play Process Proteins Proteomics Public Health RNA Resistance Resistance development Role Sampling Seeds Serum Side Signal Transduction Signaling Molecule Signaling Protein Soil Staging Stromal Cells Surface System Testing Therapeutic Therapeutic Effect Tissue Microarray Tissues Transcriptional Activation Treatment Cost Tropism Tumor Biology Work Xenograft Model angiogenesis antibody-dependent cell cytotoxicity base beta catenin chemotherapy conventional therapy cost curative treatments cytotoxic cytotoxicity design effective therapy extracellular high throughput screening improved in vivo insight knock-down loss of function migration model design neoplastic cell new therapeutic target novel novel marker potential biomarker protein expression public health relevance receptor scaffold small hairpin RNA small molecule inhibitor targeted treatment therapeutic target tool transcriptome sequencing tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Background: Multiple Myeloma (MM) is a cancer of plasma cells that accumulate in the bone marrow (BM). Despite recent advances in treatments, it remains incurable and there is urgent need of novel and more effective therapies. However, there has recently surfaced a new treatment paradigm that shows great promise to improve patient outcome by disrupting the tropism that the BM microenvironment, the `soil', plays on MM cells, the `seeds'. Since BM angiogenesis is a hallmark of MM progression that correlates with disease stage, it became evident that among the interactions between MM cells and the BM microenvironment, those with BM endothelial cells (BMECs) must play an important role in MM progression. Preliminary data: During studies of the interaction of MM cells with the BM microenvironment, we uncovered a critical role of canonical Wnt signaling, a conduit for cell-cell communication and tropism culminating in transcriptional activation of pro- migration, proliferation, and survival genes. The terminal effector of Wnt signaling is a transcriptional complex that includes two other signaling proteins, ß-catenin and BCL9. Moreover, during immunohistochemical studies using BM tissue microarrays, we observed restricted and high-level BCL9 expression in BMECs but not other BM cells. In addition, using proteomic analysis we have documented that extracellular Cyclophilin A (eCyPA) is a downstream transcriptional target of the Wnt/ß-catenin/BCL9 complex, which is secreted by BMECs but not other BM stromal cells and promote pleiotropic signaling changes in MM including enhanced expression of CD14, the know receptor of eCyPA. Furthermore, knockdown of either eCyPA in BMECs or CD147 in MM cells markedly decreased migration and proliferation of MM cells. Working hypothesis: (i) signaling from BMECs is essential for MM progression; (ii) eCyPA plays critical roles in the signaling output from BMECs that modulate migration, invasion, colonization, growth, survival, and drug resistance of MM cells. Thus, targeting the interaction between eCyPA and its cognate receptor CD147 on MM cells is therapeutic for MM, particularly for cases with acquired resistance to standard chemotherapy. Goals: (i) to further characterize the role of BMECs in MM progression, (ii) to validate the role of the eCyPA/CD147 signaling complex as therapeutic target for MM, (iii) to identify and functionally characterize additional signaling molecules secreted by BMECs that promote MM progression, and (iii) to develop a high throughput screening assay to identify small molecule inhibitors of eCyPA/CD147 interaction for future development of targeted therapies for MM. Expected results: i) validate role of eCyPA/CD147 signaling complex as effective nontoxic target for MM therapy; ii) identification of novel potential biomarkers of MM progression and therapeutic targets. Broader implications for medicine: Development of more effective targeted therapies for MM and other hematologic malignancies that express CD147 and 'home in' the BM.

描述（由申请人提供）：背景：多发性骨髓瘤（MM）是一种浆细胞在骨髓（BM）中积聚的癌症。尽管最近在治疗方面取得了进展，但它仍然无法治愈，迫切需要新的和更有效的治疗方法。然而，最近出现了一种新的治疗模式，其显示出通过破坏BM微环境（“土壤”）对MM细胞（“种子”）的向性来改善患者结果的巨大希望。由于BM血管生成是与疾病阶段相关的MM进展的标志，因此很明显，在MM细胞与BM微环境之间的相互作用中，具有BM内皮细胞（BMEC）的那些必须在MM进展中发挥重要作用。初步数据：在MM细胞与BM微环境的相互作用的研究期间，我们发现了典型Wnt信号传导的关键作用，其是细胞-细胞通信和向性的管道，最终导致促迁移、增殖和存活基因的转录激活。Wnt信号传导的末端效应子是一种转录复合物，包括另外两种信号蛋白β-连环蛋白和BCL 9。此外，在使用BM组织微阵列的免疫组织化学研究中，我们观察到BCL 9在BMEC中的有限和高水平表达，而不是其他BM细胞。此外，使用蛋白质组学分析，我们已经证明细胞外亲环蛋白A（eCyPA）是Wnt/β-连环蛋白/BCL 9复合物的下游转录靶标，其由BMEC而不是其他BM基质细胞分泌，并促进MM中的多效性信号传导变化，包括eCyPA的已知受体CD 14的表达增强。此外，敲低BMEC中的eCyPA或MM细胞中的CD 147显著降低MM细胞的迁移和增殖。工作假设：（i）来自BMEC的信号传导对于MM进展至关重要;（ii）eCyPA在来自BMEC的信号传导输出中起关键作用，所述信号传导输出调节MM细胞的迁移、侵袭、定殖、生长、存活和耐药性。因此，靶向eCyPA与MM细胞上其同源受体CD 147之间的相互作用对于MM是治疗性的，特别是对于对标准化疗具有获得性抗性的病例。目标：（i）进一步表征BMEC在MM进展中的作用，（ii）验证eCyPA/CD 147信号传导复合物作为MM治疗靶标的作用，（iii）鉴定和功能性表征由BMEC分泌的促进MM进展的另外的信号传导分子，和（iii）开发高通量筛选测定以鉴定eCyPA的小分子抑制剂。预期结果：i）验证eCyPA/CD 147信号传导复合物作为MM治疗的有效无毒靶点的作用; ii）鉴定MM进展和治疗靶点的新型潜在生物标志物。对医学的更广泛影响：开发更有效的MM和其他表达CD 147和BM“归巢”的血液恶性肿瘤靶向治疗。