Selective targeting of a Rho GTPase mutant for peripheral T cell lymphoma treatment

项目摘要/摘要|该项目的首要目标是开发针对 外周T细胞淋巴瘤(PTCL)，是一组不同的侵袭性淋巴瘤，起源于T细胞或自然 杀伤细胞和缺乏护理标准。目前PTCL的治疗选择是有限的，因为缺乏 有效的靶向治疗和对这种退化性疾病的分子病因学的不完全了解。 在这项应用中，该团队的目标是通过开发针对嵌合体的新型蛋白分解来解决这一关键差距 (PROTAC)和重新利用现有药物治疗伴有TET2和RHOA基因缺陷的PTCL(G17V为 热点突变)。PTCL T细胞中TET2和RHOA基因突变共存的研究 患者，而不是其他类型的血液肿瘤，使其成为靶向治疗的理想靶点 发展。我们进一步发现，TET2和RHOA之间的致癌协同作用驱动Vav1- 钙调神经磷酸酶(CaN)-NFAT信号轴增强NFAT活化促进T细胞恶性转化 细胞。这些新的发现导致研究小组假设，针对这种致癌协同作用可以有效地 减轻肿瘤负担。加快临床相关动物的机械性和转化性研究 模型，该团队已经产生了基因改造的小鼠模型，它概括了PTCL类基因 以及PTCL的主要疾病特征。利用独特的转基因小鼠模型，新的- RHOA-G17V突变体的三维结构测定及突变体RHOA特异性结合蛋白的结构辅助筛选 和降解物，以及一套探测GTP酶信号的分子工具，该团队唯一适合于 领导拟议的研究。在具体目标1中，该团队将开发专为RHOA(G17V)量身定做的PROTAC降解器 并在体外细胞系统中测试它们的抗肿瘤作用。在特定的目标2中，研究小组将测试抗淋巴瘤 突变的RHOA降解物在体内的疗效以及旨在抑制两者的联合疗法 上游突变的RHOA和下游的CaN/NFAT活性与FDA批准的药物(PROTAC+他克莫司)有关。 该团队还将探索作用机制，以更好地揭示支撑致病机制的信息 PTCL。如果成功，这项拟议的研究将阐明以前被低估的潜在机制 T细胞淋巴瘤，并建立针对PTCL的新型干预方法的临床前理论基础。 从我们的研究中获得的临床前试验结果将构成立即进行后续临床试验的基础。 值得注意的是，PROTAC针对RhoA(G17V)的战略将提供针对特定目标的第一个例子之一 用于淋巴瘤治疗的GTP酶。考虑到大约50%的比例，潜在的好处将是巨大的- 70%的血管免疫母细胞性T细胞淋巴瘤(PTCL的一个亚型)患者存在RhoA(G17V)突变 但缺乏有效的治疗选择。尽管我们提出了一项仅限于PTCL的研究，但其方法和药物 我们开发的候选药物可以应用于其他癌症的研究。

Project Summary / Abstract | The overarching goal of this project is to develop targeted therapies for peripheral T cell lymphoma (PTCL), a diverse group of aggressive lymphomas that develop from T cells or natural killer cells and lack standards of care. The current therapeutic options for PTCL are limited due to the lack of effective targeted therapeutics and incomplete understanding of the molecular etiology for this dismissal disease. In this application, the team aims to address this critical gap by developing novel Proteolysis Targeting Chimera (PROTAC) and repurposing existing drugs to treat PTCL with genetic defects in TET2 and RHOA (G17V as the hot spot mutation). The co-existence of TET2 and RHOA mutations is frequently detected in T cells of PTCL patients but not in other types of hematological neoplasms, making it an ideal target for targeted therapeutics development. We further discovered that an oncogenic synergy between TET2 and RHOA drives Vav1- calcineurin (CaN)-NFAT signaling axis to augment NFAT activation and promote malignant transformation of T cells. These novel findings led the team to hypothesize that targeting this oncogenic synergy can effectively reduce tumor burden. To accelerate the mechanistic and translational studies with clinically-relevant animal models, the team has generated genetically modified mouse models that recapitulate the PTCL-like genotype and the major disease hallmarks of PTCL. Capitalizing on the unique transgenic mouse models, the newly- determined 3D structure of the RHOA-G17V mutant, structure-aided screening of mutant RHOA-specific binders and degraders, as well as a suite of molecular tools to probe GTPase signaling, the team is uniquely suited to lead the proposed studies. In Specific Aim 1, the team will develop PROTAC degraders tailored for RHOA(G17V) and test their anti-tumor effects in cellular systems ex vivo. In Specific Aim 2, the team will test the anti-lymphoma efficacy of mutant RHOA degraders in vivo, as well as a combination therapy designed to suppress both upstream mutant RHOA and downstream CaN/NFAT activity with FDA-approved drugs (PROTAC + Tacrolimus). The team will also probe the mechanism of action to better inform the pathogenic mechanism underpinning PTCL. If successful, the proposed study will illuminate previously-underappreciated mechanisms underlying T-cell lymphoma, and establish the preclinical rationale for novel interventional approaches against PTCL. Preclinical testing results obtained from our study will form the basis for immediate follow-on clinical trials. Notably, the PROTAC strategy against RhoA(G17V) will provide one the first examples of targeting a specific GTPase for lymphoma treatment. The potential benefit will be significant considering that apporximately 50- 70% patients with angioimmunoblastic T-cell lymphoma (a subgroup of PTCL) harbor the RhoA(G17V) mutation but lack effective treatment options. Although we propose a study limited to PTCL, the approaches and drug candidates that we develop can be applied to encompass the study of other cancers.