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

描述（由申请方提供）：胰腺癌（PDAC）中KRAS癌基因突变激活的频率基本上为100%，以及异常KRAS功能在胰腺癌发展和肿瘤维持中的强有力的验证作用，表明抗Ras抑制剂将为PDAC提供非常有效的治疗。也许抗Ras抑制剂最有前途的途径是Ras效应物信号传导的拮抗剂。然而，这些努力已经复杂的众多效应途径，可能会促进Ras介导的肿瘤发生。我们最近的研究验证了RalGEF-Ral小GT3途径作为KRAS依赖性PDAC生长的关键介质。因此，我们假设Ral信号传导的抑制将提供PDAC生长的有效抑制。我们确定了两种不同的药理学方法，用于阻断RalGEF-Ral信号传导，抑制剂香叶基香叶基转移酶-I和Aurora-A蛋白激酶翻译后修饰的Ral，建立了两个令人兴奋的可能性来实现这一点。因此，我们提出的研究的主要目的将是对这些方向进行进一步的临床前评价，包括对最先进的人原发性异种移植物和KRAS驱动的基因工程小鼠模型的研究，以进一步研究PDAC生长中RalGEF-Ral激活的机制，并确定阻断PDAC中Ral功能的其他方向。我们提出了四个具体的目的[1]确定是否抑制香叶基香叶基转移酶-I（GGTI-2417）和Ral GT3膜结合足以抑制胰腺肿瘤发生和转移，[2]确定Aurora-A激酶抑制剂的抗肿瘤活性是否（MP529和MLN 8237）需要抑制RalA功能以及是否有其他蛋白激酶调节RalGT 3功能，[3]确定是否GGT酶-I和/或Aurora-A抑制（单独或与吉西他滨组合）足以在KRAS驱动的小鼠模型中损害患者来源的原发性胰腺异种移植物的生长以及胰腺肿瘤发生和转移，并且[4]鉴定Ral GT3激活的临床相关转录靶标，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方法过渡到PDAC的I/II期临床试验

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