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

选择性靶向 Rho GTPase 突变体治疗外周 T 细胞淋巴瘤

• 批准号: 10721439
• 负责人: Yubin Zhou
• 金额: $ 22.44万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721439
• 关键词: Acceleration; Address; Affect; Animal Model; B-Cell Lymphomas; Bioinformatics; Biology; Biometry; Blood Cells; CD4 Positive T Lymphocytes; Calcineurin; Calcineurin inhibitor; Caring; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; DNA Methylation; Diagnosis; Disease; Drug usage; Epigenetic Process; Etiology; FDA approved; FK506; Family member; Genes; Genetic; Genomics; Genotype; Goals; Guanosine Triphosphate Phosphohydrolases; Hand; Hematologic Neoplasms; Hematopoietic Neoplasms; Homologous Gene; Hot Spot; Human; Immunoblastic Lymphadenopathy; Intervention; Lead; Lesion; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Mature T-Lymphocyte; Modification; Molecular; Mus; Mutation; Natural Killer Cells; Oncogenic; Pathogenicity; Pathway interactions; Patients; Penetrance; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pilot Projects; Play; Positioning Attribute; Preclinical Testing; Progression-Free Survivals; Property; Protac; RHOA gene; Records; Signal Pathway; Signal Transduction; Somatic Mutation; Structure; Subgroup; System; T-Cell Lymphoma; T-Cell Transformation; T-Lymphocyte; Tacrolimus; Technology; Test Result; Testing; Therapeutic; Transcription Factor AP-1; Transgenic Mice; Tumor Burden; United States; antitumor effect; cancer cell; clinically relevant; design; drug candidate; effective therapy; efficacy evaluation; improved; in vivo; mouse model; mutant; new therapeutic target; novel; nuclear factors of activated T-cells; pre-clinical; public health relevance; rho; rho GTP-Binding Proteins; screening; small molecule; synergism; targeted treatment; therapeutic development; therapy design; three dimensional structure; tool; transcription factor; translational study; tumor; tumor growth

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.

项目摘要 /摘要|该项目的总体目标是开发针对性的疗法 周围T细胞淋巴瘤（PTCL）是一种从T细胞或天然发展的多种侵袭性淋巴瘤 杀手细胞和缺乏护理标准。由于缺乏，当前PTCL的治疗选择受到限制 有效的靶向治疗方法和对这种解雇疾病的分子病因的不完全理解。 在此应用程序中，该团队旨在通过开发针对嵌合体的新型蛋白水解来解决这一关键差距 （PROTAC）和重新利用现有药物以在TET2和RHOA中使用遗传缺陷治疗PTCL（G17V作为 热点突变）。在PTCL的T细胞中经常检测到TET2和RHOA突变的共存 患者但不在其他类型的血液学肿瘤中，使其成为靶向治疗的理想目标 发展。我们进一步发现，TET2和Rhoa之间的致癌协同作用驱动Vav1- 钙调神经酶（CAN）-NFAT信号轴以增强NFAT激活并促进T的恶性转化 细胞。这些新颖的发现使团队假设针对这种致癌协同作用可以有效地 减轻肿瘤负担。用临床上的动物加速机械和翻译研究 模型，该团队生成了基因修饰的小鼠模型，该模型概括了PTCL样基因型 以及PTCL的主要疾病标志。利用独特的转基因鼠标模型，新近 确定的RhoA-G17V突变体的3D结构，突变体Rhoa特异性粘合剂的结构辅助筛选 和降级器以及一套分子工具来探测GTPase信号，团队非常适合 领导拟议的研究。在特定的目标1中，团队将开发针对Rhoa量身定制的Protac Degraders（G17V） 并测试其在体内细胞系统中的抗肿瘤作用。在特定的目标2中，团队将测试抗淋巴瘤 突变的Rhoa降解器在体内的功效，以及旨在抑制两者的联合疗法 上游突变体RhoA和下游可以使用FDA批准的药物（Protac +他克莫司）进行/NFAT活性。 该团队还将探究行动机制，以更好地告知基础的致病机制 PTCL。如果成功，拟议的研究将阐明以前未经认可的机制 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构成立即进行后续临床试验的基础。 值得注意的是，针对RhoA（G17V）的Protac策略将为针对特定的第一个例子提供一个例子 用于淋巴瘤治疗的GTPase。考虑到50- 70％的血管免疫细胞T细胞淋巴瘤（PTCL亚组）患者含有RhoA（G17V）突变 但是缺乏有效的治疗选择。尽管我们提出了一项限于PTCL的研究，但方法和药物 我们开发的候选人可以应用于涵盖其他癌症的研究。