Molecular Targeting of Diffuse Large B-cell Lymphoma

描述（由申请人提供）：BCL6是b细胞淋巴瘤中最常见的癌基因，并在两种最常见的淋巴瘤：弥漫性大b细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）的大多数患者中组成性表达。许多BCL6阳性肿瘤需要BCL6的持续存在以维持其生存。BCL6是BTB/POZ转录抑制因子家族的一员。BCL6通过募集SMRT、N-CoR和BCoR协同抑制蛋白介导基因沉默。BCL6的BTB结构域提供了一个延伸的沟槽状表面，SMRT、N-CoR和BCoR共抑制因子的线性肽可以高亲和力地结合到该表面。BCL6抑制ATR和TP53等关键检查点调控基因需要这种蛋白-蛋白相互作用。我们推测，阻断BCL6 BTB结构域协同抑制因子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学途径来增强。沿着这些思路，我们开发了一种BCL6的拟肽抑制剂，称为RI-BPI（逆转录逆转BCL6拟肽抑制剂），具有良好的效力，药代动力学，毒性特征和功效。该提案汇集了在拟肽药物设计，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综合经验，实现以下目标：1)开发RI-BPI的化学模拟物；2)在体外和体内确定RI-BPI及其衍生物单独或联合在DLBCL细胞系中杀死细胞的机制和功效；3)确定原发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RI-BPI在bcl -6阳性DLBCL患者中的安全性、活性和最佳剂量。在融资期结束时，我们希望将拟肽BCL6抑制剂药物推向II期临床试验。公共卫生相关性：b细胞淋巴瘤是美国第四大最常见的癌症形式，这种疾病的几个亚型是无法治愈的。这些肿瘤中最常见的致癌基因是BCL6转录抑制蛋白。该提案将确定作用机制，完善并转化为临床试验特异性BCL6靶向治疗拟肽药物，我们预测这将对改善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.