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

描述（由申请人提供）：胰腺癌（PDAC）中KRAS癌基因突变激活的基本频率为100%，加上KRAS异常功能在胰腺癌发展和肿瘤维持中的强大验证作用，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效应信号的拮抗剂。然而，这些努力由于可能促进ras介导的肿瘤发生的众多效应通路而变得复杂。我们最近的研究证实了RalGEF-Ral小GTPase途径是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的生长。我们确定了阻断RalGEF-Ral信号的两种不同的药理学方法，香叶基香叶基转移酶i和Aurora-A蛋白激酶翻译后修饰的抑制剂，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将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在PDAC生长中的激活机制，并确定阻断PDAC中Ral功能的其他方向。我们提出了四个特定目的：[1]确定抑制香叶基香叶基转移酶i （GGTI-2417）和Ral GTPase膜结合是否足以抑制胰腺肿瘤的发生和转移，[2]确定Aurora-A激酶抑制剂（MP529和MLN8237）的抗肿瘤活性是否需要抑制RalA功能，以及其他蛋白激酶是否调节Ral GTPase功能。[3]在kras驱动的小鼠模型中确定GGTase-I和/或Aurora-A抑制（单独或联合吉西他滨）是否足以损害患者来源的原发性胰腺异种移植物的生长和胰腺肿瘤的发生和转移，[4]确定Ral GTPase激活的临床相关转录靶点，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方法转化为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 PUBLIC HEALTH RELEVANCE: Pancreatic cancer remains one of the deadliest cancers. We have shown that the RalGEF-Ral pathway is clinically and functionally important in pancreatic cancer. The goals of this proposal are to study the RalGEF- Ral pathway as a therapeutic target for pancreatic cancer treatment by using both available pharmacologic approaches and by identifying novel approaches to target this pathway.