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Role of RABL6A-PP2A in neuroendocrine tumors

RABL6A-PP2A在神经内分泌肿瘤中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要