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

项目总结/摘要|该项目的总体目标是开发针对以下疾病的靶向疗法： 外周T细胞淋巴瘤（PTCL）是一组从T细胞或自然淋巴细胞发展而来的侵袭性淋巴瘤， 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 有效的靶向治疗和不完全的理解，这种解雇疾病的分子病因。 在这项应用中，该团队的目标是通过开发新的蛋白水解靶向嵌合体来解决这一关键差距 （PROTAC）并重新利用现有药物来治疗具有TET 2和RHOA遗传缺陷的PTCL（G17 V作为 热点突变）。在PTCL的T细胞中经常检测到TET 2和RHOA突变的共存 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TET 2和RHOA之间的致癌协同作用驱动Vav 1- 钙调神经磷酸酶（CaN）-NFAT信号轴增强NFAT活化并促进T细胞恶性转化 细胞这些新的发现使研究小组假设，靶向这种致癌协同作用可以有效地 降低肿瘤负荷。加速临床相关动物的机制和转化研究 模型，该小组已经产生了遗传修饰的小鼠模型，重现了PTCL样基因型 和PTCL的主要疾病特征。利用独特的转基因小鼠模型，新的- 确定RHOA-G17 V突变体的3D结构，突变体RHOA特异性结合剂的结构辅助筛选 和降解剂，以及一套探测GT3信号的分子工具，该团队非常适合 领导拟议的研究。在具体目标1中，该团队将开发针对RHOA（G17 V）量身定制的PROTAC降能器 并在离体细胞系统中测试它们的抗肿瘤作用。在具体目标2中，该团队将测试抗淋巴瘤 突变RHOA降解剂在体内的功效，以及设计用于抑制两者的联合疗法 上游突变体RHOA和下游CaN/NFAT活性与FDA批准的药物（PROTAC +他克莫司）。 该团队还将探索作用机制，以更好地了解致病机制 PTCL。如果成功的话，这项研究将阐明以前未被充分认识的潜在机制。 T细胞淋巴瘤，并建立针对PTCL的新型介入方法的临床前原理。 从我们的研究中获得的临床前测试结果将成为立即进行后续临床试验的基础。 值得注意的是，针对RhoA（G17 V）的PROTAC策略将提供靶向特定的免疫调节剂的第一个实例。 用于淋巴瘤治疗。考虑到大约50- 70%的血管免疫母细胞性T细胞淋巴瘤（PTCL的一个亚组）患者携带RhoA（G17 V）突变 但缺乏有效的治疗选择。虽然我们提出的研究仅限于PTCL，但方法和药物 我们开发的候选人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.