Project 3: Combination inhibition of ERK for pancreatic cancer treatment

项目总结 KRAS癌基因在95%的胰腺导管癌(PDAC)中发生突变。有相当多的 实验证据表明，突变KRAS的持续表达对PDAC的维持是必不可少的。它是 人们普遍认为，有效的抗KRAS疗法将对胰腺癌产生重大影响， 抑制KRAS效应信号被认为是最有希望进入临床的方向。在……里面 特别是，相当大的努力和兴趣现在集中在Raf-MEK-ERK丝裂原激活的抑制剂上 蛋白激酶(MAPK)级联反应。然而，RAF和MEK抑制剂对RAS的疗效有限，甚至没有效果。 突变的癌症，主要是由于癌细胞的适应和ERK的重新激活来克服抑制物的作用。 这些发现促进了ERK抑制剂的开发，最近有四种抑制剂进入临床 评估。其中，BVD-523，一种靶向亚纳摩尔范围内ERK1和ERK2的小分子 是进入肿瘤学临床试验的领先化合物(NCT01781429)。在我们修订后的提案中，我们现在 提供大量的BVD-523临床前和临床分析，以支持我们的 学习。本研究的创新之处在于研究了一种一流的ERK直接抑制剂及其应用 无偏见的基因和化学文库筛选，以确定组合疗法，以克服其限制 用于PDAC。我们还解决了我们在先前提交的关于未定义临床的问题 学习。我们提出了四个具体目标，以促进BVD-523用于PDAC治疗的临床开发。 我们将：(1)临床评估BVD-523对PDAC患者的抗肿瘤活性和反应的生物标志物； (2)鉴定KRAS突变体PDAC对BVD-523的获得性抗性的分子机制；(3)鉴定 克服从头耐药性并使BVD-523治疗具有细胞毒性的联合抑制剂方法； 以及(4)评估与BVD-523的联合抑制策略在最新有机化合物中的抗肿瘤活性 胰腺癌的培养和小鼠模型。我们的目标是找出克服从头开始的组合 和获得性抵抗力，以及细胞静态和瞬时反应以及正常组织毒性 临床评价。完成后，我们的研究将确定ERK治疗的预测性生物标记物 反应，使我们能够确定最有效的ERK组合，以便在临床研究中进行测试。

PROJECT SUMMARY The KRAS oncogene is mutated in ~95% of pancreatic ductal adenocarcinoma (PDAC). There is considerable experimental evidence that continued expression of mutant KRAS is essential for PDAC maintenance. It is generally accepted that an effective anti-KRas therapy will have a significant impact on pancreatic cancer, with inhibition of KRAS effector signaling considered the most promising direction for advancement to the clinic. In particular, considerable effort and interest is now focused on inhibitors of the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. However, Raf and MEK inhibitors have shown limited to no efficacy in RAS- mutant cancers, due primarily to cancer cell adaptation and ERK reactivation to overcome the inhibitor action. These findings have prompted the development of ERK inhibitors, with four inhibitors recently entering clinical evaluation. Among them, BVD-523, a small molecule that targets ERK1 and ERK2 in the sub-nanomolar range is the leading compound entering oncology clinical trials (NCT01781429). In our revised proposal, we now provide substantial preclinical and clinical analyses of BVD-523 that support the rationale and feasibility of our studies. The innovation of our studies is our focus on a first-in-class direct inhibitor of ERK and applying unbiased genetic and chemical library screens to identify combination therapies to overcome limitations for its use for PDAC. We also address the concern raised in our previous submission regarding undefined clinical studies. We propose four Specific Aims to advance the clinical development of BVD-523 for PDAC treatment. We will: (1) clinically evaluate BVD-523 anti-tumor activity and biomarkers of response in patients with PDAC; (2) identify molecular mechanisms for acquired resistance to BVD-523 in KRAS-mutant PDAC; (3) identify combination inhibitor approaches that overcome de novo resistance and render BVD-523 treatment cytotoxic; and (4) assess combination inhibitor strategies with BVD-523 for anti-tumor activity in state-of-the-art organoid culture and mouse models of pancreatic cancer. Our goal is to identify combinations that overcome de novo and acquired resistance, as well as cytostatic and transient responses and normal tissue toxicity, for future clinical evaluation. When completed, our study will have identified predictive biomarkers for ERK treatment response, allowing us to identify the most effective ERK combinations to be tested in clinical studies.