Rational Combination of MAP4K4 Inhibition and Immunotherapy in Pancreatic Cancer

总结/摘要： 胰腺导管腺癌（PDAC）仍然是非常致命的，5年生存率低于 百分之九。由于其对常规治疗的广泛耐药性，PDAC预计将成为第二常见的 到2030年，美国癌症相关死亡的原因。致癌性KRAS突变几乎是一致的， PDAC，影响超过90%的患者。突变型KRAS是肿瘤表型的关键驱动因素， 过度激活KRAS，允许持续增殖，逃避凋亡，以及促进 转移和化学抗性的发展。尽管KRAS在PDAC病理生物学中的重要性 和广泛的研究旨在发现RAS导向的治疗方法，没有FDA批准的药物， 针对靶向RAS; RAS家族蛋白在很大程度上被认为是“不可药物化的”。因此需要 以确定可替代的药物靶点或更好的方法，以期改善患者的治疗效果。 已知炎症途径在许多癌症中起重要作用，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。我们确定 MLK 3是一种新的激酶，由TNFα激活，在胰腺癌发病机制中发挥作用。最近我们 鉴定了MLK 3上游激酶MAP 4K 4，它也被TNFα激活，这可能表明，TNFα- MAP 4K 4-MLK 3轴可能在胰腺癌中起作用，这一点被最近的一项报告所证实， MAP 4K 4高表达的PDAC患者预后最差。考虑到我们的观察，我们治疗了 用MAP 4K 4的特异性抑制剂GNE-495的PDAC动物模型。有趣的是，GNE-495能够 改善临床前动物模型中的PDAC，显著减少基质和增加细胞死亡， 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细胞， GNE-495的作用。我们合理地用4-1BB激动性抗体治疗动物， 激活效应T细胞。GNE-495沿着4-1BB单抗的联合治疗对 动物存活率和肿瘤中几乎不存在基质/纤维组织增生。本建议的总体目标是 阐明MAP 4K 4在PDAC中的作用，并制定合理的方法来联合收割机使用MAP 4K抑制剂和 免疫疗法来战胜胰腺癌中心目标将通过以下方式实现：（1）确定 MAP 4K 4在PDAC中的作用，（2）确定MAP 4K 4抑制在TME中的影响，和（3）确定MAP 4K 4抑制在TME中的影响。 MAP 4K抑制沿着免疫治疗对宿主免疫的影响。 在完成这三个目标后，我们期望，第一，我们将能够确立 PDAC中的MAP 4K 4。第二，我们将建立靶向MAP 4K 4的临床意义，沿着 合理的免疫疗法作为胰腺癌的替代治疗策略。

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.