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癌基因突变激活的频率基本上为100%，加上KRAS功能异常在胰腺癌发生和肿瘤维持中的强大验证作用，认为抗RAS抑制剂将为PDAC提供非常有效的治疗方法。也许最有希望的抗RAS抑制剂的途径是RAS效应信号的拮抗剂。然而，可能促进RAS介导的肿瘤发生的众多效应通路使这些努力变得复杂。我们最近的研究证实，Ralgef-ral小GTPase通路是KRAS依赖的PDAC生长的关键中介。因此，我们假设抑制Ral信号将有效地抑制PDAC的生长。我们确定了两种截然不同的阻断Ralgef-ral信号的药物途径，即香叶基香叶基转移酶-I抑制剂和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将是对这些方向进行进一步的临床前评估，包括最新的人类原代异种移植和KRAS驱动的基因工程小鼠模型的研究，进一步研究Ralgef-ral在PDAC生长中激活的机制，并确定在PDAC中阻断Ral功能的其他方向。[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，以及额外的蛋白激酶是否调节Ral GTP酶功能；[3]确定GGTase-I和/或Aurora-A抑制(单独或联合吉西他滨)是否足以抑制患者来源的原发胰腺移植瘤的生长和胰腺肿瘤的发生和转移和[4]确定Ral GTP酶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