IRAK4 As a Novel Immunotherapeutic Target in Pancreatic Ductal Adenocarcinoma

胰腺癌患者的预后仍然令人沮丧。有效的治疗显然是一种未得到满足的医疗需求 对这些病人来说。除了让一小部分患者受益的手术外，目前的标准治疗 由剧毒且有效几率不到50%的强化疗组成。对于那些 最初受益于化疗，快速进展是不可避免的。免疫疗法的前景，虽然已经 在其他癌症类型中出现，但未能显示出对胰腺癌患者的好处。治疗性的 因此，突破必须来自胰腺癌生物学的新发现。我们现在最近 首次在文献中发现胰腺癌细胞通过激活与生俱来的 免疫，一种通常在细胞受到伤害或入侵时被召唤的自卫机制 微生物。在这样做的过程中，胰腺癌细胞变得高度侵袭并对 化疗药物。我们的方法是通过以下方式去激活胰腺癌细胞中的这种防御机制 抑制控制天然免疫的主开关--白细胞介素1受体相关激酶4(IRAK4) 路径。通过这样做，我们发现胰腺癌细胞变得非常虚弱，并且 易受化疗的影响。在这个前提下，我们现在有了进一步的潜在影响的发现，我们 计划确认和追求以下三个目标： 1.目标1：我们发现IRAK4的存在对于支持转化的生长和细胞是必不可少的 信号是由致癌的KRAS驱动的，这是一种几乎在所有胰腺癌中都存在的遗传事件。我们 将探索机制细节，并确定失去IRAK4是否会阻碍KRAS驱动 利用人胰腺癌细胞系和最新遗传小鼠进行胰腺肿瘤的实验研究 模特们。如果被证明是真的，这些结果可能会对其他KRAS突变癌症类型产生影响。 2.目标2：我们已经建立了一种IRAK4缺陷的胰腺癌小鼠模型，我们计划 描述理解全球IRAK4丢失的后果，就像药理学将发生的那样 抑制，在胰腺癌进展中。此外，我们还将专门研究免疫的作用 IRAK4在胰腺癌生长中的作用，如果IRAK4抑制剂是 在未来进入临床试验。 3.目标3：我们的初步数据显示，抑制IRAK4使免疫治疗在遗传上有效 老鼠模型。在这个目标中，我们将测试两种新型的、高效的IRAK4抑制剂，最终目标是 将这些发现转化为临床试验。

The prognosis for pancreatic cancer patients remains dismal. Effective therapy is clearly an unmet medical need for these patients. Aside from surgery which benefits a small fraction of patients, current standard treatment consists of strong chemotherapy that is highly toxic and with less than 50% chance of working. For those who initially benefit from chemotherapy, rapid progression is inevitable. The promise of immunotherapy, while already realized in other cancer types, has failed to show benefit for pancreatic cancer patients. Therapeutic breakthrough must therefore come from novel discoveries in the biology of pancreatic cancer. We now recently found, for the first time in literature, that pancreatic cancer cells “armored” themselves by activating the innate immunity, a self-defense mechanism that is usually summoned when cells are injured or invaded by microorganisms. In doing so pancreatic cancer cells become highly aggressive and resistant to chemotherapeutics. Our approach is to “deactivate” such defense mechanism in pancreatic cancer cells by inhibiting Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), the master switch that controls the innate immune pathway. By doing so we found that pancreatic cancer cells become greatly weakened and are much more vulnerable to chemotherapy. On this premise we have now made further potentially impactful findings that we plan to confirm and pursue in the following three aims: 1. Aim 1: We found that presence of IRAK4 is essential for supporting transformed growth and cellular signaling driven by oncogenic KRAS, a genetic event that is present in almost all pancreatic cancer. We will explore the mechanistic detail and determine whether loss of IRAK4 will impede KRAS-driven pancreatic tumorigenesis using human pancreatic cancer cell lines and state-of-the-art genetic mouse models. If shown to be true, these results could have impact on other KRAS-mutant cancer types. 2. Aim 2: We have generated an IRAK4-deficient pancreatic cancer mouse model that we plan to characterize to understand the consequence of global IRAK4 loss, as will happen with pharmacologic inhibition, in pancreatic cancer progression. In addition, we will specifically study the role of immune IRAK4 in pancreatic cancer growth, which will yield clinically useful information if IRAK4 inhibitors are advanced into clinical trials in the future. 3. Aim 3: Our preliminary data shows that IRAK4 inhibition renders immunotherapy effective in genetic mouse model. In this aim we will test two novel, highly potent IRAK4 inhibitors, with the ultimate goal of translating these findings into clinical trials.