Rational Combination of MAP4K4 Inhibition and Immunotherapy in Pancreatic Cancer

摘要/摘要： 胰腺导管腺癌(PDAC)仍然非常致命，5年生存率不到 9%。由于对常规治疗的广泛抵抗，预计PDAC将成为第二常见的治疗方法。 到2030年，美国与癌症相关的死亡原因。致癌的KRAS突变在 PDAC，影响90%以上的患者。突变的KRAS是肿瘤表型的关键驱动因素，并导致 对KRAS的过度激活，允许持续的增殖，逃避凋亡，以及促进 转移与化疗耐药的发展。尽管KRAS在PDAC病理生物学中的重要性 和旨在发现RAS导向疗法的广泛研究，目前还没有FDA批准的药物 靶向RAS；RAS家族蛋白在很大程度上被认为是“不可用药的”。因此，有必要 确定可替代药物靶点(S)或更好的方法，希望改善患者结果。 众所周知，炎症途径在许多癌症中发挥着重要作用，包括胰腺癌。 许多报告表明，炎症和胰腺癌之间存在直接联系。我们确认了 MLK3是一种新的由肿瘤坏死因子α激活的蛋白，在胰腺癌的发病机制中起着重要作用。最近我们 发现了一种MLK3上游的激酶，MAP4K4，它也被肿瘤坏死因子α激活，提示可能是肿瘤坏死因子α- MAP4K4-MLK3轴可能在胰腺癌中发挥作用，最近的一份报告证实了这一点。 MAP4K4高表达的PDAC患者预后不良。考虑到我们的观察，我们治疗了 应用MAP4K4特异性抑制剂GNE-495建立PDAC动物模型。有趣的是，GNE-495能够 在临床前动物模型中改善PDAC，显著减少间质和增加细胞死亡 癌变的导管细胞。由于免疫细胞在癌症治疗中起着至关重要的作用，我们检查了外周免疫。 对GNE-495没有影响的隔间。我们合理地用4-1BB激动型抗体治疗动物 激活效应器T细胞。GnE-495与4-1BB单抗联合治疗对慢性粒细胞白血病疗效显著。 肿瘤无动物存活，几乎无间质/间质增生。这项提议的总体目标是 目的：阐明MAP4K4在PDAC中的作用，探讨MAP4K抑制剂和MAP4K4联合应用的合理途径。 克服胰腺癌的免疫疗法。中心目标将通过以下方式实现：(1)界定 MAP4K4在PDAC中的作用，(2)确定MAP4K4抑制在TME中的影响，以及(3)确定影响 MAP4K抑制和免疫治疗对宿主免疫的影响。 在完成这三个目标之后，我们的期望是，第一，我们能够确立 PDAC中的MAP4K4。其次，我们将建立靶向MAP4K4的临床意义，以及 胰腺癌替代治疗策略的合理化免疫治疗。

Summary/Abstract: Pancreatic Ductal Adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of less than 9%. Due to its widespread resistance to conventional therapy, PDAC is expected to be the second most common cause of cancer-related death in the United States by 2030. Oncogenic KRAS mutations are nearly uniform in PDAC, affecting over 90% of patients. The mutant KRAS is a key driver in the neoplastic phenotype, and leads to hyper-activation of KRAS, permitting for sustained proliferation, the evasion of apoptosis, as well as facilitating metastasis and the development of chemo-resistance. In spite of the importance of KRAS in PDAC pathobiology and extensive research aimed at the discovery of RAS-directed therapeutics, there are no FDA-approved drugs directed to target RAS; and RAS family proteins are largely considered `un-druggable'. Therefore, there is a need to identify either alternative- druggable target(s) or better approaches in hopes of improving patient outcomes. The inflammatory pathway is known to play significant roles in many cancer, including pancreatic cancer. Number of reports suggest that there is a direct link between inflammation and pancreatic cancer. We identified MLK3, a novel kinase that is activated by TNFα and plays role in pancreatic cancer pathogenesis. Recently we identified an MLK3 upstream kinase, MAP4K4, which is also activated by TNFα, suggesting perhaps, TNFα- MAP4K4-MLK3 axis might play a role in pancreatic cancer, which was corroborated by a recent report indicating worst outcomes in PDAC patient with high expression of MAP4K4. Considering our observation, we treated animal model of PDAC with a specific inhibitor of MAP4K4, GNE-495. Interestingly, the GNE-495 was able to ameliorate PDAC in the pre-clinical animal model, a significant decrease in stroma and increased cell death in cancerized ductal cells. Since immune cells play vital roles in cancer therapy, we examined peripheral immune compartment that had no effect of GNE-495. We rationalized to treat animals with 4-1BB agonistic antibody to activate effector T cells. The combined treatment of GNE-495 along with 4-1BB mab had profound effect on animal survival and almost stroma/Desmoplasia was absent in tumors. The overall objective of this proposal is to elucidate the role of MAP4K4 in PDAC and strategize a rational approach to combine MAP4K inhibitor and immunotherapies to overcome pancreatic cancer. The central objective will be addressed by: (1) defining the role of MAP4K4 in PDAC, (2) determining the impact of MAP4K4 inhibition in TME, and (3) determining impact of MAP4K inhibition along with immunotherapy on host immunity. Upon completion of these three aims, it is our expectation, that first, we will be able to establish the role of MAP4K4 in PDAC. Second, we would establish clinical significance of targeting MAP4K4, along with rationalized immunotherapy for an alternative pancreatic cancer treatment strategy.