Mining B-catenin/BCL9 transcriptional complex for Multiple Myeloma therapeutics

挖掘 B-catenin/BCL9 转录复合物用于多发性骨髓瘤治疗

• 批准号: 8463474
• 负责人: RUBEN D CARRASCO
• 金额: $ 32.54万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463474
• 关键词: Affect; African American; BCL9 gene; Biological Assay; Biological Models; Bone Marrow; Bone Marrow Cells; Caucasians; Caucasoid Race; Cell Line; Cell Proliferation; Cell Survival; Cells; Colon Carcinoma; Complex; Data; Development; Disease; Disease Progression; Early Diagnosis; Elderly; Epithelial; Event; Gene Expression Profiling; Gene Targeting; Gene Transfer; Genes; Genetic; Genetic Transcription; Goals; Health; Hematologic Neoplasms; Heterogeneity; High-Dose Chemotherapy with Autologous Stem Cell Transplant; Homeostasis; Human; Immunoblot Analysis; In Vitro; Individual; Investigation; Laboratories; Lead; Ligands; Maintenance; Malignant Neoplasms; Mediating; Medicine; Mesenchymal; Mining; Modeling; Molecular; Molecular Genetics; Molecular Target; Multiple Myeloma; Mutation; Non-Hodgkin' s Lymphoma; Oncogenes; Pathogenesis; Pathway interactions; Patients; Peptides; Play; Pre-Clinical Model; Property; Proteins; Public Health; RNA Interference; Reporter; Role; Signal Transduction; Small Interfering RNA; Technology; Testing; Therapeutic; Therapeutic Intervention; Tropism; Tumor Suppressor Proteins; Validation; Work; alpha helix; base; beta catenin; chromatin immunoprecipitation; cytokine; effective therapy; extracellular; gain of function; improved; in vivo; in vivo Model; inhibitor/antagonist; loss of function; loss of function mutation; model design; nanoparticle; neoplastic cell; new therapeutic target; novel; overexpression; protein complex; response; small hairpin RNA; small molecule; therapeutic development; therapeutic target; therapy resistant; tool; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is the second most frequent hematological cancer in the US after non- Hodgkin's lymphoma with about 20,000 individuals succumbing to this dreaded disease each year in the US alone. Despite recent advances in its treatment, the median survival remains at 6 years, with only 10% of patients surviving at 10 years. Therefore there is an urgent need for new and effective therapeutic approaches, particularly those targeting common molecular pathways involved in disease progression and maintenance, and shared across different MM subtypes. Our laboratory has devoted significant effort towards the identification of the molecular genetic events in this malignancy, with the goals of improving early detection and providing new molecular targets for the development of more effective therapies for this cancer. Preliminary data: In our previous studies we have documented that the Wnt/B-catenin/BCL9 pathway is one of such pathway involved in MM disease progression and maintenance. Specifically we have found that: i) BCL9 is overexpressed in most MM cells but it is not expressed in the normal cellular counterpart where they originate, ii) BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic and angiogenic properties to myeloma cells, iii) RNAi suppressed expression of either 2-catenin or BCL9 inhibits MM tumor growth in vitro and in vivo, and iv) stapled peptides of the BCL9 HD2 domain inhibit 2-catenin/BCL9-dependent transcriptional activity in MM cells. Working hypothesis: The 2-catenin/BCL9 transcriptional complex itself and some of the downstream transcriptional targets are novel important therapeutic targets in MM. Goals: Our goals are to validate and functionally characterize novel B-catenin/BCL9 transcriptional target genes and to explore the possible role of the 2-catenin/BCL9 protein complex itself as therapeutic target in MM. Experimental tools: To test our hypothesis we will use as tools stabilized alpha-helices of BCL9 to disrupt B-catenin/BCL9 protein interaction and stabilized nano particles to deliver BCL9 small interfering RNAs to myeloma cells. In addition, we will use our expertise with lentiviral-based gene transfer technologies for functional validation, using gain- and loss-of-function approaches as well as well-established in vitro and in vivo model systems that reflect the heterotopic interactions between the MM cell and bone marrow microenvironment. Expected results: i) to identify and validate novel downstream B-catenin/BCL9 downstream genes which could be used as therapeutic targets in MM, ii) to functionally characterize and validate the role of the B-catenin/BCL9 transcriptional complex itself as a novel therapeutic target in MM. Probable implications to Medicine: The potential implications are: i) to find novel genes involved in the pathogenesis and progression of MM, ii) to find novel molecular targets to effectively treat MM, and iii) to develop preclinical models for designing and assessing target-based therapeutic approaches in MM and other hematologic malignancies associated with dysregulated Wnt activity.

描述（由申请人提供）：多发性骨髓瘤（MM）是美国仅次于非霍奇金淋巴瘤的第二大常见血液癌症，仅在美国每年就有约20，000人死于这种可怕的疾病。尽管最近在治疗方面取得了进展，但中位生存期仍为6年，只有10%的患者存活10年。因此，迫切需要新的有效的治疗方法，特别是那些靶向参与疾病进展和维持的共同分子途径，并在不同的MM亚型中共享的方法。我们的实验室已经投入了大量的努力，对这种恶性肿瘤的分子遗传事件的识别，提高早期检测和提供新的分子靶点，为这种癌症的更有效的治疗方法的发展的目标。初步数据：在我们以前的研究中，我们已经证明Wnt/B-catenin/BCL 9通路是参与MM疾病进展和维持的此类通路之一。具体而言，我们发现：i）BCL 9在大多数MM细胞中过表达，但在它们起源的正常细胞对应物中不表达，ii）BCL 9通过赋予骨髓瘤细胞增强的增殖、转移和血管生成特性来促进肿瘤进展，iii）RNAi抑制2-连环蛋白或BCL 9的表达在体外和体内抑制MM肿瘤生长，和iv）BCL 9 HD2结构域的钉合肽抑制MM细胞中的2-连环蛋白/BCL 9依赖性转录活性。工作假设：2-catenin/BCL 9转录复合物本身和一些下游转录靶点是MM中新的重要治疗靶点。目标：我们的目标是验证和功能表征新的B-catenin/BCL 9转录靶基因，并探索2-catenin/BCL 9蛋白复合物本身作为MM中治疗靶点的可能作用。为了验证我们的假设，我们将使用BCL 9的稳定化α-螺旋作为工具来破坏B-连环蛋白/BCL 9蛋白质相互作用，并使用稳定化纳米颗粒来将BCL 9小干扰RNA递送到骨髓瘤细胞。此外，我们将利用我们的专业知识与基于慢病毒的基因转移技术进行功能验证，使用获得和丧失功能的方法以及完善的体外和体内模型系统，反映了MM细胞和骨髓微环境之间的异位相互作用。预期成果：i）鉴定和验证可用作MM中的治疗靶标的新型下游B-连环蛋白/BCL 9下游基因，ii）功能性表征和验证B-连环蛋白/BCL 9转录复合物本身作为MM中的新型治疗靶标的作用。i）发现参与MM发病机制和进展的新基因，ii）发现有效治疗MM的新分子靶标，和iii）开发临床前模型，用于设计和评估MM和其他与Wnt活性失调相关的血液恶性肿瘤中基于靶点的治疗方法。