Role of RABL6A-PP2A in neuroendocrine tumors

RABL6A-PP2A在神经内分泌肿瘤中的作用

• 批准号: 10800877
• 负责人: Goutham Narla
• 金额: $ 1.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10800877
• 关键词: Address; Affect; Automobile Driving; Cell Cycle; Cell Proliferation; Cell Survival; Cell model; Clinical; Combined Modality Therapy; Data; Dependence; Development; Disease; Event; FRAP1 gene; Genetic; Growth; Guanosine Triphosphate Phosphohydrolases; Half-Life; Holoenzymes; Human; In Vitro; Incidence; Invaded; Islet Cell Tumor; Knowledge; Malignant Neoplasms; Measures; Molecular; Molecular Analysis; Neoplasm Metastasis; Neuroendocrine Tumors; Oncogenic; Oncoproteins; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phosphorylation; Population; Progression-Free Survivals; Proliferating; Protein Dephosphorylation; Protein phosphatase; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; RB1 gene; Receptor Protein-Tyrosine Kinases; Regulation; Research; Resources; Role; Signal Transduction; Testing; Therapeutic; Tumor Cell Migration; Tumor Suppressor Proteins; Validation; Work; advanced disease; angiogenesis; anti-cancer; c-myc Genes; cancer therapy; effective therapy; efficacy evaluation; experimental study; improved; in vivo; inhibitor; insight; mTOR Inhibitor; migration; mouse model; neoplastic cell; novel strategies; novel therapeutics; overexpression; pharmacologic; phosphoproteomics; protein activation; response; small molecule; targeted treatment; tumor; tumor growth; tumor progression

Project Summary / Abstract Neuroendocrine tumors (NETs) are incurable, clinically challenging malignancies that are rising in incidence. Although tumors grow slowly, they progress relentlessly and lack effective therapies once they become metastatic. Many patients with advanced NETs will die from their disease. Greater understanding of mechanisms driving NET progression and metastasis is needed to inform new therapies and improve patient outcomes. We discovered a RABL6A-PP2A pathway that promotes pancreatic NET (PNET) pathogenesis. RABL6A (RAB-like GTPase) is upregulated in patient PNETs and is required for PNET proliferation and survival. RABL6A acts through multiple mechanisms that are only partly defined, including inhibition of tumor suppressors (p27, RB1) and activation of oncogenic pathways (MYC, AKT-mTOR). A common regulator of all those factors is protein phosphatase 2A (PP2A), a powerful tumor suppressor whose role in NETs has not been explored. We found that RABL6A activates AKT-mTOR signaling in PNETs by inhibiting PP2A. In turn, RABL6A is down regulated by PP2A although the molecular mechanism by which these two proteins inhibit each other's function is unknown. Excitingly, specific `small molecule activators of PP2A' (called SMAPs) suppress PNET cell proliferation and survival in a RABL6A-dependent manner and abolish tumor growth in vivo. These findings support a novel strategy for PNET therapy involving PP2A reactivation. However, the role of RABL6A and PP2A in NET progression is only partly understood and their importance in NET metastasis is not known. This multi-PI study draws upon the collective knowledge of both PIs and their unique expertise / resources in NETs (Quelle) and PP2A (Narla) to test the central hypothesis that the RABL6A-PP2A pathway is a critical driver of NET progression and response to targeted therapies. Aim 1 will determine the mechanisms of RABL6A-PP2A reciprocal regulation. Aim 2 will define the roles and interdependence of RABL6A and PP2A in NET progression and metastasis. Aim 3 will establish the importance of the RABL6A- PP2A alterations in NET pathogenesis and the efficacy of pathway targeted combination therapies. This project will provide new insights into molecular events driving NET progression and metastasis while establishing the efficacy of promising NET therapeutics, thus addressing a critical gap in NET research that may ultimately improve patient outcomes. Moreover, this work builds upon an emerging strategy for anticancer therapy (i.e., pharmacological reactivation of PP2A), and may have broad cancer relevance beyond NETs given the importance of RABL6A overexpression and PP2A inactivation in other tumor types.

项目概要/摘要 神经内分泌肿瘤（NET）是无法治愈的、临床上具有挑战性的恶性肿瘤，其发病率正在上升。 肿瘤虽然生长缓慢，但一旦发展就会无情地进展，缺乏有效的治疗方法。 转移性的。许多患有晚期 NET 的患者将死于该病。更深入地了解 需要驱动 NET 进展和转移的机制来为新疗法提供信息并改善患者状况 结果。 我们发现了一条促进胰腺 NET (PNET) 发病机制的 RABL6A-PP2A 通路。 RABL6A （RAB 样 GTP 酶）在患者 PNET 中表达上调，并且是 PNET 增殖和存活所必需的。 RABL6A 通过多种机制发挥作用，但这些机制仅部分明确，包括抑制肿瘤 抑制因子（p27、RB1）和致癌途径激活（MYC、AKT-mTOR）。所有人的共同监管者 这些因子是蛋白磷酸酶 2A (PP2A)，它是一种强大的肿瘤抑制因子，其在 NET 中的作用尚未被证实。 被探索过。我们发现 RABL6A 通过抑制 PP2A 激活 PNET 中的 AKT-mTOR 信号传导。反过来， RABL6A 被 PP2A 下调，尽管这两种蛋白抑制的分子机制 彼此的功能未知。令人兴奋的是，特定的“PP2A 小分子激活剂”（称为 SMAP） 以 RABL6A 依赖性方式抑制 PNET 细胞增殖和存活，并消除肿瘤生长 体内。这些发现支持涉及 PP2A 重新激活的 PNET 治疗新策略。然而，角色 RABL6A 和 PP2A 在 NET 进展中的作用仅部分了解，它们在 NET 转移中的重要性尚不明确 不知道。这项多 PI 研究利用了两位 PI 的集体知识及其独特的专业知识/ NETs (Quelle) 和 PP2A (Narla) 中的资源来测试 RABL6A-PP2A 的中心假设 NET 通路是 NET 进展和靶向治疗反应的关键驱动因素。目标1将决定 RABL6A-PP2A 相互调节的机制。目标 2 将定义角色和相互依赖性 RABL6A 和 PP2A 在 NET 进展和转移中的作用。目标 3 将确立 RABL6A 的重要性- PP2A 在 NET 发病机制中的改变以及通路靶向联合疗法的功效。 该项目将为驱动 NET 进展和转移的分子事件提供新的见解，同时 确定有前途的 NET 疗法的功效，从而解决 NET 研究中的一个关键差距 最终可能会改善患者的治疗效果。此外，这项工作建立在一种新兴的抗癌策略的基础上 疗法（即 PP2A 的药理学重新激活），并且可能具有除 NET 之外的广泛癌症相关性 考虑到 RABL6A 过表达和 PP2A 失活在其他肿瘤类型中的重要性。