Molecular Targeting of Diffuse Large B-cell Lymphoma

描述（由申请人提供）：BCL 6是B细胞淋巴瘤中最常见的癌基因，并且在大多数患有两种最常见形式的淋巴瘤的患者中组成性表达：弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）。许多这些BCL 6阳性肿瘤需要BCL 6的持续存在以维持其存活。BCL 6是BTB/POZ转录抑制因子家族的成员。BCL 6通过募集SMRT、N-CoR和BCoR辅阻遏蛋白介导其对基因沉默的影响。BCL 6的BTB结构域提供了一个延伸的沟状表面，来自SMRT、N-CoR和BCoR辅阻遏物的线性肽可以高亲和力结合到该表面。这种蛋白质-蛋白质相互作用是BCL 6抑制关键检查点调控基因如ATR和TP 53所必需的。我们假设，设计用于封闭BCL 6 BTB结构域辅阻遏物结合沟的药物将阻断BCL 6抑制其关键靶基因的能力，并迫使淋巴瘤细胞进行细胞死亡，这可以通过靶向互补生物途径来增强。沿着这些路线，我们已经开发了一种称为RI-BPI（反转BCL 6拟肽抑制剂）的BCL 6拟肽抑制剂，其具有良好的效力、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，目标是：1）开发RI-BPI的化学模拟物，2）在体外和体内确定RI-BPI和衍生物单独和组合在DLBCL细胞系谱中的细胞杀伤机制和功效，3）离体确定原代DLBCL对BPI的响应并鉴定预测对RI-BPI的响应的生物标志物，最后4）将BCL-6靶向治疗转化为临床，并确定BCL-6阳性DLBCL患者中RI-BPI的安全性、活性和最佳剂量。到资助期结束时，我们预计拟肽BCL 6抑制剂药物将进入II期临床试验。

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.