Targeting Ras-Ral GEF-Ral Effector Signaling for Pancreatic Cancer Treatment

靶向 Ras-Ral GEF-Ral 效应信号传导用于胰腺癌治疗

• 批准号: 8608427
• 负责人: Jen Jen Yeh
• 金额: $ 28.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-08 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608427
• 关键词: Basic Science; Clinical; Clinical Trials; Collaborations; Comprehensive Cancer Center; Data; Development; Diagnostic; Extramural Activities; Frequencies; Funding; Genetically Engineered Mouse; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Human; KRAS2 gene; Knowledge; Laboratories; Large Intestine Carcinoma; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Membrane; Monomeric GTP-Binding Proteins; Neoplasm Metastasis; Oncogenes; PGGT1B gene; Pancreas; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Post-Translational Protein Processing; Preparation; Protein Kinase; Ras Inhibitor; Research; Research Personnel; Role; Signal Transduction; Work; Xenograft procedure; aurora-A kinase; cancer therapy; clinically relevant; drug discovery; effective therapy; experience; gemcitabine; human STK6 protein; inhibitor/antagonist; interest; kinase inhibitor; mouse model; novel strategies; pancreas xenograft; pancreatic tumorigenesis; preclinical evaluation; professor; protein geranylgeranyltransferase; public health relevance; therapeutic target; translational study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The essentially 100% frequency of mutational activation of the KRAS oncogene in pancreatic cancers (PDAC), together with the strong validated role of aberrant KRAS function in pancreatic cancer development and tumor maintenance, argues that anti-Ras inhibitors will provide a very effective therapy for PDAC. Perhaps the most promising avenues for anti-Ras inhibitors are antagonists of Ras effector signaling. However, these efforts have been complicated by the multitude of effector pathways that may promote Ras-mediated oncogenesis. Our recent studies validated the RalGEF-Ral small GTPase pathway as a critical mediator of KRAS-dependent PDAC growth. We therefore hypothesize that inhibition of Ral signaling will provide effective inhibition of PDAC growth. Our identification of two distinct pharmacologic approaches for blocking RalGEF-Ral signaling, inhibitors of geranylgeranyltransferase-I and Aurora-A protein kinase posttranslational modification of Ral, establishes two exciting possibilities to accomplish this. Therefore, the main objectives of our proposed studies will be to perform further preclinical evaluation of these directions, including studies on state-of-the art human primary xenografts and KRAS driven genetically-engineered mouse models, to further investigate the mechanisms of RalGEF-Ral activation in PDAC growth, and to identify additional directions for blocking Ral function in PDAC. We propose four Specific Aims to [1] determine if inhibition of geranylgeranyltransferase-I (GGTI-2417) and Ral GTPase membrane association are sufficient to inhibit pancreatic tumorigenesis and metastasis, [2] determine if the anti-tumor activity of Aurora-A kinase inhibitors (MP529 and MLN8237) requires the inhibition of RalA function and whether additional protein kinases regulate Ral GTPase function, [3] determine whether GGTase-I and/or Aurora-A inhibition (alone or in combination with gemcitabine) are sufficient to impair the growth of patient-derived primary pancreatic xenografts and pancreatic tumorigenesis and metastasis in a KRAS-driven mouse model, and [4] identify clinically relevant transcriptional targets of Ral GTPase activation, as diagnostic or therapeutic targets, of RalA- and RalB-mediated oncogenesis. Our long-term goal is to transition anti-Ral approaches into Phase I/II clinical trials for PDAC

描述（由申请人提供）：胰腺癌 (PDAC) 中 KRAS 癌基因的突变激活频率基本上为 100%，再加上异常 KRAS 功能在胰腺癌发展和肿瘤维持中的经过强有力验证的作用，表明抗 Ras 抑制剂将为 PDAC 提供非常有效的治疗方法。也许抗 Ras 抑制剂最有前途的途径是 Ras 效应信号传导的拮抗剂。然而，由于多种可能促进 Ras 介导的肿瘤发生的效应途径，这些努力变得复杂化。我们最近的研究验证了 RalGEF-Ral 小 GTP 通路是 KRAS 依赖性 PDAC 生长的关键介质。因此，我们假设抑制 Ral 信号传导将有效抑制 PDAC 生长。我们鉴定了两种不同的药理学方法来阻断 RalGEF-Ral 信号传导，即香叶基香叶基转移酶-I 抑制剂和 Ral 的 Aurora-A 蛋白激酶翻译后修饰，为实现这一目标建立了两种令人兴奋的可能性。因此，我们提出的研究的主要目标是对这些方向进行进一步的临床前评估，包括对最先进的人类原代异种移植物和KRAS驱动的基因工程小鼠模型的研究，以进一步研究RalGEF-Ral的机制PDAC 生长中的激活，并确定阻断 PDAC 中 Ral 功能的其他方向。我们提出了四个具体目标 [1] 确定香叶基香叶基转移酶-I (GGTI-2417) 和 Ral GTPase 膜关联的抑制是否足以抑制胰腺肿瘤发生和转移，[2] 确定 Aurora-A 激酶的抗肿瘤活性抑制剂（MP529 和 MLN8237）需要抑制 RalA 功能，以及是否需要额外的蛋白激酶调节 Ral GTPase 功能，[3] 确定是否GGTase-I 和/或 Aurora-A 抑制（单独或与吉西他滨联合）足以损害 KRAS 驱动的小鼠模型中患者来源的原发性胰腺异种移植物的生长以及胰腺肿瘤的发生和转移，并且 [4] 经临床鉴定Ral GTPase 激活的相关转录靶点，作为 RalA 和 RalB 介导的肿瘤发生的诊断或治疗靶点。我们的长期目标是将抗 Ral 方法转变为 PDAC 的 I/II 期临床试验

项目成果

UV activation of polymeric high aspect ratio microstructures: ramifications in antibody surface loading for circulating tumor cell selection.

• DOI: 10.1039/c3lc50618e
• 发表时间: 2014-01-07
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Jackson JM;Witek MA;Hupert ML;Brady C;Pullagurla S;Kamande J;Aufforth RD;Tignanelli CJ;Torphy RJ;Yeh JJ;Soper SA
• 通讯作者: Soper SA