Pathologic BIM Suppression & Pharmacologic BH3 Replacement in B-Cell Lymphoma

描述（由申请人提供）：BCL-2家族包括一个重要的蛋白质网络，控制细胞的生存或死亡决定。BIM是BCL-2家族的促凋亡BH 3蛋白，是B细胞稳态的主要调节剂，其功能抑制被认为是B细胞淋巴瘤的关键致病因素。该提案的目标是研究和调节B细胞中凋亡途径的这种关键的、失调的组分，并应用机制见解来推进用于在难治性淋巴瘤中重新激活细胞死亡的新型治疗策略。我假设BIM BH 3在触发细胞死亡方面的效力反映了其参与多种关键蛋白质靶点和死亡途径的能力，并且使用烃钉合肽对BIM的“死亡结构域”进行药理学替换将恢复细胞死亡，从而在B细胞淋巴瘤中获得治疗益处。我将应用多学科方法来（1）测试烃钉合的BIM BH 3螺旋重新激活B细胞淋巴瘤中由不同的凋亡阻断机制驱动的死亡程序的能力，（2）鉴定BIM SAHB的明确蛋白质靶点，以将细胞活性与原位作用机制联系起来，（3）确定药理学BIM BH 3替代在人和鼠B细胞淋巴瘤的小鼠模型中的治疗潜力。通过交织化学，淋巴瘤生物学和发育治疗学，我的目标是对BH 3-only蛋白BIM的促凋亡潜力产生新的机制见解，并确定如何利用这种独特的BH 3死亡结构域来重新激活不同B细胞淋巴瘤中的细胞死亡。由国际公认的导师，合作者和顾问组成的多元化团队领导的为期5年的综合培训计划，在合成化学，免疫学，细胞凋亡生物学和临床血液学/肿瘤学领域具有专业知识，将为LaBelle博士发展成为一名独立研究者提供理想的培训环境，在化学生物学和癌症医学的界面上具有独特的专业知识。 公共卫生相关性：复发性和难治性B细胞淋巴瘤源于癌细胞建立各种阻止自然细胞死亡的强大障碍的能力。通过交织化学，淋巴瘤生物学和临床前研究，我的目标是定义BIM的易感性模式和蛋白质靶点，BIM是BCL-2家族网络的一种有效的死亡激活蛋白，负责触发淋巴瘤细胞死亡，并提出一种新的策略来恢复BIM功能，使用钉合肽。我们相信，拟议中的研究，采用新的研究工具和原型疗法，将提供新的见解的生物学和化疗耐药B细胞淋巴瘤的治疗。 个别评审员的书面评论和标准评分在下面的“评论”部分以基本上未经编辑的形式提供。请注意，这些评论和标准评分是在会议之前准备的，在审查会议上进行任何讨论之后可能没有进行修订。上文“讨论的简历和摘要”部分总结了委员会的最终意见。

DESCRIPTION (provided by applicant): The BCL-2 family comprises an essential network of proteins that govern the cell's decision to live or die. BIM, a pro-apoptotic BH3-only protein of the BCL-2 family is a master regulator of B-cell homeostasis and its functional suppression is believed to be a key pathogenic factor in B-cell lymphoma. The goal of this proposal is to investigate and modulate this critical, deregulated component of the apoptotic pathway in B-cells and apply the mechanistic insights to advance a novel therapeutic strategy for reactivating cell death in treatment- refractory lymphoma. I hypothesize that the potency of BIM BH3 in triggering cell death reflects its capacity to engage a diversity of key protein targets and death pathways, and that pharmacologic replacement of BIM's "death domain" using a hydrocarbon-stapled peptide will restore cell death for therapeutic benefit in B-cell lymphoma. I will apply a multidisciplinary approach to (1) test the capacity of a hydrocarbon-stapled BIM BH3 helix to reactivate the death program in B-cell lymphomas driven by distinct mechanisms of apoptotic blockade, (2) identify the explicit protein targets of BIM SAHB to link cellular activity to in situ mechanism of action, (3) determine the therapeutic potential of pharmacologic BIM BH3 replacement in mouse models of human and murine B-cell lymphoma. By intertwining chemistry, lymphoma biology, and developmental therapeutics, I aim to generate fresh mechanistic insight into the pro-apoptotic potency of the BH3-only protein BIM and determine how this unique BH3 death domain can be harnessed to reactivate cell death in diverse B-cell lymphomas driven by distinct and clinically-relevant chemoresistance mechanisms. A 5-year comprehensive training program led by a diverse team of internationally-recognized mentors, collaborators, and advisors with expertise in the fields of synthetic chemistry, immunology, apoptosis biology, and clinical hematology/oncology will provide an ideal training environment for Dr. LaBelle's development into an independent investigator with unique expertise at the interface of chemical biology and cancer medicine. PUBLIC HEALTH RELEVANCE: Relapsed and treatment-refractory B-cell lymphoma arises from the cancer cell's ability to establish a variety of formidable roadblocks that prevent natural cell death. By intertwining chemistry, lymphoma biology, and preclinical studies, I aim to define the susceptibility patterns and protein targets of BIM, a potent death- activating protein of the BCL-2 family network, responsible for triggering lymphoma cell death and advance a novel strategy to restore the BIM functionality using a stapled peptide. We believe the proposed studies, which employ novel research tools and prototype therapeutics, will provide fresh insight into the biology and treatment of chemoresistant B-cell lymphoma. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.