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：
9512894
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/9512894
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 Endothelial Cells Enzyme-Linked Immunosorbent Assay Future Genes Genetic Transcription Goals Growth Hematologic Neoplasms Home environment Immune In Vitro Individual Light Malignant - descriptor Malignant Neoplasms Measures Mediating Medicine Modeling Multi-Drug Resistance Multiple Myeloma Mus Natural History Neoplasms Non-Hodgkin&apos s Lymphoma Normal Cell Output Pathogenesis Patient-Focused Outcomes Patients Plasma Cells Play Process Proteomics Public Health RNA Resistance Resistance development Role Sampling Seeds Serum Side Signal Transduction Signaling Molecule Signaling Protein Soil 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 progression marker protein B protein expression public health relevance receptor scaffold small hairpin RNA small molecule inhibitor targeted treatment therapeutic evaluation 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（由适用提供）：背景：多发性骨髓瘤（MM）是积聚在骨髓（BM）中的浆细胞的癌。尽管最近的治疗方法取得了进步，但它仍然无法治愈，并且迫切需要新颖，更有效的疗法。然而，最近有一个新的治疗范式涌现，该范式通过破坏了BM微环境（土壤'，在MM细胞上玩耍，“种子”）的巨大前景，可以改善患者的结局。由于BM血管生成是MM进展的标志，与疾病阶段相关，因此证明在MM细胞与BM微环境之间的相互作用中，患有BM内皮细胞（BMEC）的人必须在MM进展中起重要作用。初步数据：在对MM细胞与BM微环境的相互作用的研究期间，我们发现了规范Wnt信号传导的关键作用，即细胞 - 细胞通信和潮流的渠道，最终导致在迁移，增殖，增殖和存活基因的转录激活中。 Wnt信号传导的末端效应子是一种转录复合物，其中包括另外两个信号蛋白β-catenin和bcl9。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BMEC而非其他BM细胞的受限和高级BCL9表达。此外，使用蛋白质组学分析，我们已经记录了细胞外环蛋白A（ECYPA）是Wnt/ß-catenin/bcl9复合物的下游转录靶标，该靶标由BMEC分泌，而不是其他BM Stromal细胞分泌，而不是其他BM基质细胞，并促进了MM的Pleiotiotigropic信号变化，包括CD14的CD14 ecipta，包括CD14的表达增强。此外，MM细胞中BMEC或CD147中的ECYPA敲低显着降低了MM细胞的迁移和增殖。工作假设：（i）BMEC的信号对于MM进展至关重要；（ii）ECYPA在调节MM细胞的迁移，入侵，定植，生长，生长，生存和耐药性的BMEC信号输出中起关键作用。这是针对ECYPA及其同源受体CD147在MM细胞上的相互作用的治疗方法，这是MM的治疗性，特别是对于获得标准化疗的耐药性的病例。 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相互作用，用于未来开发靶疗法的MM。预期结果：i）验证ECYPA/CD147信号传导复合物作为MM治疗的有效无毒靶标； ii）鉴定MM进展和治疗靶标的新型潜在生物标志物。对医学的更广泛的影响：开发更有效的靶向疗法，用于MM和其他表达CD147和“ Home in” BM中的血液学恶性肿瘤。