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个未满足的医疗需求 对于这些患者。除了手术使一小部分患者受益外，目前的标准治疗 包括强化疗，毒性很高，工作机会不到50%。对于那些谁 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 在其他癌症类型中实现，未能显示对胰腺癌患者的益处。治疗 因此，突破必须来自胰腺癌生物学的新发现。我们现在最近 在文献中首次发现，胰腺癌细胞通过激活先天的 免疫力是一种自我防御机制，通常在细胞受到损伤或入侵时被召唤。 微生物的在这样做的过程中，胰腺癌细胞变得高度侵袭性和耐药性。 化疗药物我们的方法是通过以下方式“灭活”胰腺癌细胞中的这种防御机制： 抑制白细胞介素-1受体相关激酶4（IRAK 4），这是控制先天免疫的主开关， 通路通过这样做，我们发现胰腺癌细胞变得非常虚弱， 易受化疗影响在这个前提下，我们现在已经取得了进一步的潜在影响力的发现，我们 计划确认和追求以下三个目标： 1.目的1：我们发现IRAK 4的存在对于支持转化生长和细胞增殖是必不可少的。 由致癌KRAS驱动的信号传导，这是一种存在于几乎所有胰腺癌中的遗传事件。我们 我将探索机制细节，并确定IRAK 4的丢失是否会阻碍KRAS驱动的 使用人胰腺癌细胞系和最先进的遗传小鼠的胰腺肿瘤发生 模型如果被证明是真的，这些结果可能会对其他KRAS突变癌症类型产生影响。 2.目的2：我们已经建立了IRAK 4缺陷胰腺癌小鼠模型，我们计划 表征以了解整体IRAK 4丢失的后果，如药理学 抑制胰腺癌进展。此外，我们将专门研究免疫的作用， IRAK 4在胰腺癌生长中的作用，如果IRAK 4抑制剂被用于治疗胰腺癌， 在未来进入临床试验。 3.目的3：我们的初步数据表明，IRAK 4抑制使免疫治疗在遗传学上有效。 小鼠模型在这个目标中，我们将测试两种新的，高效的IRAK 4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.