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.

项目总结/摘要|该项目的总体目标是开发针对 外周 T 细胞淋巴瘤 (PTCL)，一组由 T 细胞或天然细胞发展而来的侵袭性淋巴瘤。 杀伤细胞并且缺乏护理标准。由于缺乏有效的治疗手段，目前 PTCL 的治疗选择有限。 有效的靶向治疗和对这种解雇疾病的分子病因学的不完全了解。 在此应用中，该团队旨在通过开发新型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 TET2 和 RHOA 基因缺陷的 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，但不适用于其他类型的血液肿瘤，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- 钙调神经磷酸酶 (CaN)-NFAT 信号轴增强 NFAT 激活并促进 T 细胞恶性转化 细胞。这些新发现使研究小组假设，针对这种致癌协同作用可以有效地 减少肿瘤负荷。加速临床相关动物的机制和转化研究 模型，该团队已经生成了基因改造小鼠模型，再现了 PTCL 样基因型 以及 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-G17V 突变体的 3D 结构，结构辅助筛选突变体 RHOA 特异性结合物 和降解剂，以及一套用于探测 GTPase 信号传导的分子工具，该团队特别适合 领导拟议的研究。在具体目标1中，团队将开发专为RHOA(G17V)定制的PROTAC降解剂 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，团队将测试抗淋巴瘤 突变型 RHOA 降解剂在体内的功效，以及旨在抑制两者的联合疗法 上游突变体 RHOA 和下游 CaN/NFAT 活性与 FDA 批准的药物（PROTAC + 他克莫司）。 该团队还将探讨其作用机制，以更好地了解其致病机制。 PTCL。如果成功，拟议的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基本原理。 从我们的研究中获得的临床前测试结果将构成立即后续临床试验的基础。 值得注意的是，针对 RhoA(G17V) 的 PROTAC 策略将提供针对特定目标的第一个例子。 GTPase 用于淋巴瘤治疗。考虑到大约 50- 70% 的血管免疫母细胞 T 细胞淋巴瘤（PTCL 的一个亚组）患者携带 RhoA(G17V) 突变 但缺乏有效的治疗方案。尽管我们提出一项仅限于 PTCL 的研究，但方法和药物 我们开发的候选药物可以应用于其他癌症的研究。