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

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血液学癌症，仅在美国每年就有大约20,000人死于这种可怕的疾病。尽管其治疗方法最近取得了进展，但中位生存期仍为6年，只有10%的患者存活至10年。因此，迫切需要新的有效的治疗方法，特别是针对参与疾病进展和维持的共同分子途径，并在不同MM亚型中共享。我们的实验室致力于鉴别这种恶性肿瘤的分子遗传事件，目的是提高早期发现，并为开发更有效的治疗方法提供新的分子靶点。初步资料：在我们之前的研究中，我们已经证实Wnt/B-catenin/BCL9通路是参与MM疾病进展和维持的途径之一。具体来说，我们发现：i) BCL9在大多数MM细胞中过表达，但在正常细胞中不表达，ii) BCL9通过增强骨髓瘤细胞的增殖、转移和血管生成特性来促进肿瘤进展，iii) RNAi抑制2-catenin或BCL9的表达，抑制体外和体内MM肿瘤生长，iv) BCL9 HD2结构域的钉接肽抑制MM细胞中2-catenin/BCL9依赖的转录活性。工作假设：2-catenin/BCL9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/BCL9转录靶基因，并探索2-catenin/BCL9蛋白复合物本身作为MM治疗靶点的可能作用。为了验证我们的假设，我们将使用稳定的BCL9 α螺旋作为工具来破坏b -连环蛋白/BCL9蛋白的相互作用，并使用稳定的纳米颗粒将BCL9小干扰rna递送到骨髓瘤细胞。此外，我们将利用我们在慢病毒基因转移技术方面的专业知识进行功能验证，使用功能增益和功能丧失方法，以及成熟的体外和体内模型系统，反映MM细胞和骨髓微环境之间的异位相互作用。预期结果：i)鉴定和验证可作为MM治疗靶点的新型下游B-catenin/BCL9下游基因，ii)功能表征和验证B-catenin/BCL9转录复合物本身作为MM治疗靶点的作用。可能的医学意义：潜在的意义是：i)寻找参与MM发病和进展的新基因，ii)寻找有效治疗MM的新分子靶点，以及iii)建立临床前模型，用于设计和评估MM和其他与Wnt活性失调相关的血液系统恶性肿瘤的靶向治疗方法。

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.