Molecular Targeting of Diffuse Large B-cell Lymphoma

描述(申请人提供)：Bcl6是B细胞淋巴瘤中最常见的癌基因，在大多数有两种最常见的淋巴瘤形式的患者中都有表达：弥漫性大B细胞淋巴瘤(DLBCL)和滤泡性淋巴瘤(FL)。其中许多bcl6阳性肿瘤需要bcl6的持续存在才能维持生存。Bcl6是BTB/POZ转录抑制因子家族的成员。Bcl6通过SMRT、N-COR和BCOR辅阻遏子蛋白的募集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沟槽状表面，来自SMRT、N-COR和BCOR辅阻遏子的线性多肽可以高亲和力结合到该表面。BCL6需要这种蛋白质-蛋白质相互作用来抑制关键的检查点调控基因，如ATR和TP53。我们假设，旨在阻断BCL6 BTB结构域辅阻遏物结合槽的药物将阻断BCL6抑制其关键靶基因的能力，并迫使淋巴瘤细胞经历细胞死亡，这可以通过靶向互补的生物途径来增强。沿着这些思路，我们开发了一种BCL6的模拟肽抑制剂，称为RI-BPI(Retro-Inverso BCL6多肽模拟抑制剂)，具有良好的效力、药代动力学、毒性和疗效。该提案汇集了在模拟肽药物设计、淋巴瘤生物学、血液病理学和临床研究方面具有专业知识的合作科学家。他们将利用他们在这些不同领域的联合经验，目标是1)开发RI-BPI的化学模拟药物，2)确定RI-BPI及其衍生物在体外和体内一系列DLBCL细胞系中单独和联合应用的细胞杀伤机制和有效性，3)确定原代DLBCL对BPI的体外反应并确定预测RI-BPI反应的生物标志物，最后4)将BCL6靶向治疗转化为临床，并确定bcl6阳性DLBCL患者应用RI-BPI的安全性、活性和最佳剂量。到资助期结束时，我们预计将把拟肽类BCL6抑制剂药物转移到第二阶段临床试验。公共卫生相关性：B细胞淋巴瘤是美国第四种最常见的癌症，这种疾病的几种亚型是无法治愈的。这些肿瘤中最常见的致癌基因是BCL6转录抑制蛋白。这项提案将确定作用机制，改进一种特定的BCL6靶向治疗肽类药物并将其转化为临床试验，我们预计这种药物将对改善B细胞淋巴瘤患者的临床护理产生重大影响。

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.