Targeting RAS signaling with CDK and AKT inhibition in pancreatic cancer

描述（由申请人提供）：胰腺癌是美国癌症死亡的第四大原因。由于缺乏有效的治疗选择，发病率和死亡率几乎相等，因此迫切需要新的治疗方法。（1，2）许多研究已经证明Ras信号传导在胰腺癌细胞生长和发育中起关键作用，其中>90%的胰腺癌表现出激活Ras突变。(3)Ras激活具有多种作用，主要通过三个主要途径，MAPK、AKT和RAL途径。(4)我们的研究小组和其他研究人员已经表明，RAL信号传导是胰腺癌中重要的促生存信号传导途径，CDK5是RAL信号传导的另一种激活剂。（3，5，6）我们详细介绍了一项旨在通过同时抑制Ras的三个关键下游途径中的两个来破坏Ras信号传导系统的临床试验。我们提出了一项关于Akt抑制剂MK2206和强效多CDK抑制剂dinaciclib联合治疗晚期胰腺癌的I期研究，并增加了一个扩展队列，以评估初步疗效和转化终点。本研究的第一个队列将确定该组合在胰腺癌中的最大耐受剂量（MTD）以及安全性和毒性特征。随后将入组该MTD的扩展队列，以评估该组合的初步疗效以及多个相关终点。扩展队列中的患者将随机接受单药治疗一周，然后从该时间点开始进行联合治疗，并在治疗前和治疗后进行连续血液采样和肿瘤活检。该策略允许在治疗前、开始单药治疗后和添加第二种药物后进行药代动力学和药效学分析。药效学终点将侧重于AKT和RAL通路效应物和终点，作为靶点证据和潜在用途，作为该方案未来研究的治疗获益预测因子。这是一种基于强有力的临床前数据通过抑制Ras的两个关键下游途径靶向胰腺癌的新方法。我们的目标是通过为这种致命疾病提供新的治疗选择来提高胰腺癌患者的生存率。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the United States. The incidence and mortality rates are nearly equivalent due to the paucity of effective treatment options and, accordingly, new therapies are desperately needed.(1, 2) Numerous studies have demonstrated the key role that Ras signaling plays in pancreatic cancer cell growth and development, with >90% of pancreatic adenocarcinoma manifesting activating Ras mutations. (3) Ras activation has multiple effects, predominantly through three major pathways, the MAPK, AKT, and RAL pathways. (4) Our group and others have shown that RAL signaling is an important pro-survival signaling pathway in pancreatic cancer and that CDK5 is another activator of RAL signaling.(3, 5, 6) We detail a clinical trial tha aims to disrupt the Ras signaling system by using concurrent inhibition of two of the three key downstream pathways of Ras. We propose a Phase I study of the combination of MK2206, an Akt inhibitor, and dinaciclib, a potent multi-CDK inhibitor, in advanced pancreatic cancer with an added expansion cohort to assess for preliminary efficacy and translational endpoints. The first cohort of this study will be to determine the maximum tolerated dose (MTD) and the safety and toxicity profiles for this combination in pancreatic cancer. An expansion cohort at that MTD will subsequently be enrolled to assess the preliminary efficacy of this combination as well as multiple correlative endpoints. Patients in the expansion cohort will be randomized to receive single agent therapy for one week, followed by combination treatment from that point onwards with serial blood sampling and tumor biopsies pre- and post-treatment. This strategy allows for pharmacokinetic and pharmacodynamic analyses prior to treatment, after initiation of single agent, and after addition of the second agent. Pharmacodynamic endpoints will focus on AKT and RAL pathway effectors and endpoints as both proof-of-target and potential use as predictors of therapeutic benefit for future studies of this regimen. This is a novel approach to target pancreas cancer by inhibiting two key downstream pathways of Ras based on strong preclinical data. Our goal is to increase the survival of patients with pancreatic cancer by providing a new treatment option for this lethal disease.