Project 3: Combination inhibition of ERK for pancreatic cancer treatment

项目摘要 KRAS癌基因在约95%的胰腺导管腺癌（PDAC）中发生突变。有相当大 实验证据表明，突变KRAS的持续表达对于PDAC维持至关重要。是 普遍认为，有效的抗KRas治疗将对胰腺癌产生显著影响， KRAS效应物信号传导的抑制被认为是向临床发展的最有希望的方向。在 特别是，相当大的努力和兴趣现在集中在Raf-MEK-ERK有丝分裂原激活的抑制剂上。 蛋白激酶（MAPK）级联反应。然而，Raf和MEK抑制剂在RAS中显示出有限的功效或没有功效。 突变型癌症，主要是由于癌细胞适应和ERK再激活以克服抑制剂作用。 这些发现促进了ERK抑制剂的发展，最近有四种抑制剂进入临床， 评价其中，BVD-523是一种在亚纳摩尔范围内靶向ERK 1和ERK 2的小分子 是进入肿瘤临床试验的领先化合物（NCT 01781429）。在我们的修订提案中，我们现在 提供BVD-523的大量临床前和临床分析，以支持我们的 问题研究我们研究的创新之处在于我们专注于一种一流的ERK直接抑制剂， 无偏见的遗传和化学文库筛选，以确定联合疗法，以克服其局限性， 用于PDAC。我们还解决了我们之前提交的关于未定义临床 问题研究我们提出了四个具体目标，以推进BVD-523用于PDAC治疗的临床开发。 我们将：（1）临床评价BVD-523在PDAC患者中的抗肿瘤活性和反应生物标志物; (2)鉴定KRAS突变PDAC中获得性BVD-523抗性的分子机制;（3）鉴定 联合抑制剂方法克服了从头耐药性并使BVD-523治疗具有细胞毒性; 和（4）评估与BVD-523的组合抑制剂策略在最先进的类器官中的抗肿瘤活性 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 获得性耐药性，以及细胞抑制和瞬时反应和正常组织毒性， 临床评价完成后，我们的研究将确定ERK治疗的预测生物标志物 反应，使我们能够确定最有效的ERK组合进行测试，在临床研究。

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.