Molecular Targeting of Diffuse Large B-cell Lymphoma

弥漫性大 B 细胞淋巴瘤的分子靶向

• 批准号: 8208201
• 负责人: ARI M. MELNICK
• 金额: $ 57.11万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-20 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208201
• 关键词: Affinity; Animals; Antibody Formation; B-Cell Lymphomas; B-Lymphocytes; BCL1 Oncogene; BCL6 gene; BTB/POZ Domain; Binding; Biological; Biological Markers; Biology; Cell Death; Cell Line; Cells; Chemicals; Clinic; Clinical Research; Clinical Trials; Complex; DNA Damage; Data; Development; Docking; Dose; Drug Design; Drug Kinetics; Drug usage; Family; Follicular Lymphoma; Funding; Gene Silencing; Gene Targeting; Goals; Health; Hematopathology; Human; In Vitro; Lymphoma; Malignant Neoplasms; Mediating; Molecular Structure; Molecular Target; Mus; N-terminal; Normal Cell; Oncogenes; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase II Clinical Trials; Protein Family; Proteins; Regulator Genes; Repression; Repressor Proteins; Safety; Scientist; Specimen; Structure of germinal center of lymph node; Surface; TP53 gene; Toxic effect; Transcription Repressor/Corepressor; Translating; United States; Work; cell killing; clinical care; design; disorder subtype; experience; human NCOR1 protein; improved; in vivo; inhibitor/antagonist; killings; large cell Diffuse non-Hodgkin' s lymphoma; member; mimetics; peptidomimetics; protein protein interaction; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): BCL6 is the most commonly involved oncogene in B-cell lymphomas, and is expressed constitutively in a majority of patients with two most frequent forms of lymphoma: the diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma (FL). Many of these BCL6 positive tumors require the continued presence of BCL6 in order to maintain their survival. BCL6 is a member of the BTB/POZ family of transcriptional repressors. BCL6 mediates its effects on gene silencing through recruitment of the SMRT, N-CoR and BCoR corepressor proteins. The BTB domain of BCL6 provides an extended groove like surface to which a linear peptide from the SMRT, N-CoR and BCoR corepressor can bind with high affinity. This protein-protein interaction is required for BCL6 to repress critical checkpoint regulatory genes such as ATR and TP53. We hypothesize that drugs designed to occlude the BCL6 BTB domain corepressor binding groove will block the ability of BCL6 to repress its critical target genes and force lymphoma cells to undergo cell death, which could be enhanced by targeting complementary biological pathways. Along these lines, we have developed a peptidomimetic inhibitor of BCL6 called RI-BPI (retro-inverso BCL6 peptidomimetic inhibitor) with favorable potency, pharmacokinetics, toxicity profile and efficacy. The proposal brings together collaborating scientists with expertise in peptidomimetic drug design, lymphoma biology, hematopathology and clinical research. They will leverage their combined experience in these different fields with the goals of 1) Developing chemical-mimetics of RI-BPI, 2) determining the mechanism and efficacy of cell killing of RI-BPI and derivatives alone and in combination in a spectrum of DLBCL cell lines in vitro and in vivo, 3) determining the response of primary DLBCLs to BPI ex vivo and identify biomarkers predictive of response to RI-BPI, and finally 4) to translate BCL6 targeted therapy to the clinic and determine the safety, activity, and optimal dosing of RI-BPI in patients with BCL-6-positive DLBCL. By the end of the funding period, we expect to be moving peptidomimetic BCL6 inhibitor drugs into phase II clinical trials. PUBLIC HEALTH RELEVANCE: B-cell lymphomas are the fourth most common form of cancer in the United States and several subtypes of this disease are incurable. The most common causative oncogene in these tumors is the BCL6 transcriptional repressor protein. This proposal will define the mechanism of action, refine and translate to a clinical trial a specific BCL6 targeted therapy peptidomimetic drug that we predict will have a major impact on improving the clinical care for patients with B-cell lymphomas.

描述（由申请人提供）：BCL6是B细胞淋巴瘤中最常见的癌基因，并且在大多数具有两种最常见的淋巴瘤形式的大多数患者中构成表达：弥漫性大B细胞淋巴瘤（DLBCL）和卵泡淋巴瘤（FL）。这些BCL6阳性肿瘤中的许多都需要持续存在BCl6，以维持其生存。 BCL6是BTB/POZ转录阻遏物家族的成员。 Bcl6通过募集SMRT，N-COR和BCOR COREPRESSOR蛋白来介导其对基因沉默的影响。 BCl6的BTB结构域提供了一个延伸的凹槽表面，从SMRT，N-COR和BCOR COREPRESSOR的线性肽可以与高亲和力结合。 Bcl6需要这种蛋白质 - 蛋白质相互作用来抑制关键检查点调节基因，例如ATR和TP53。我们假设旨在阻断Bcl6 BTB结构核心结合凹槽的药物将阻止Bcl6抑制其关键靶基因并迫使淋巴瘤细胞经历细胞死亡的能力，这可以通过靶向互补的生物学途径来增强。沿着这些线路，我们开发了一种Bcl6的肽抑制剂，称为RI-BPI（恢复互联的Bcl6肽抑制剂），具有良好的效力，药代动力学，毒性和功效。该提案汇集了与肽药物设计，淋巴瘤生物学，血肿学和临床研究方面的专业知识的合作。他们将利用自己在这些不同领域的综合经验，其目标是1）开发RI-BPI的化学仿制药，2）单独确定RI-BPI和衍生物的细胞杀死机制和功效RI-BPI，最后4）将BCL6的靶向治疗转化为诊所，并确定BCL-6阳性DLBCL患者RI-BPI的安全性，活性和最佳剂量。到资金期结束时，我们预计将肽型BCL6抑制剂药物转移到II期临床试验中。公共卫生相关性：B细胞淋巴瘤是美国的第四种最常见的癌症形式，该疾病的几种亚型是无法治愈的。这些肿瘤中最常见的致病性癌基因是Bcl6转录抑制剂蛋白。该提案将定义作用机理，完善并转化为临床试验，特定的BCl6靶向治疗肽类药物，我们预测，该药物将对改善B细胞淋巴瘤患者的临床护理产生重大影响。