Design of MEK Inhibitor Regimens for the Treatment of Pancreatic Cancer

描述（由申请人提供）：RAS-MAP激酶信号级联是在绝大多数人胰腺癌中激活的关键途径。在对其生物输出至关重要的多种蛋白质参与者中，下游激酶MEK已成为药理学抑制的有吸引力的候选者。随着许多最近开发的MEK特异性试剂的可用性，需要努力设计临床试验，其中已经优化了给药和时间表。该提案的主要目标是系统地研究MEK抑制作为胰腺癌治疗策略，在历史上难以研究的临床前模型中使用新的成像方法。将通过引入用于MEK活性和用于诱导细胞凋亡的报告基因来修改胰腺导管腺癌的基因工程小鼠模型。这些机载分子成像报告分子的Cre依赖性诱导将使得能够基于生物发光成像监测肿瘤负荷、MEK的靶向抑制和通过细胞凋亡诱导成像的活动物中的纵向治疗反应。我们假设，当将MEK抑制剂整合到目前采用的治疗胰腺癌的化疗和放疗方案中时，将提供明显的治疗益处。然而，目前涉及慢性每日给药的范式已经成为当今药物临床试验的标准实践， 在这里进行评估。我们的分子成像方法将增加我们对靶点调节动力学与治疗结果之间关系的理解。将通过比较持续与最大靶点抑制来评价多个剂量和方案，以优化治疗。我们相信这是第一个研究进行优化MEK抑制剂治疗的基础上，生物发光成像的胰腺癌起源和增殖直接在小鼠胰腺。此外，将对一组原发性原位异种移植物进行检测，这更可能反映临床试验中遇到的异质性。扩散MRI作为早期治疗反应的替代生物标志物的前景也将被探索用于未来的临床翻译。使用新的成像替代物来检测关键信号事件可能会对胰腺癌的治疗产生重大影响，有助于早期评估患者的反应，并加快试验时间表。我们提出了一种范式转换策略，通过整合新型小鼠模型与药物-靶标相互作用的成像读数，来合理设计和优化临床试验。净影响将改善胰腺癌的治疗结果，并作为适用于其他目标和患者人群的原型方法。 公共卫生相关性：迫切需要开发更有效的治疗方法来改善胰腺癌的低生存率。合理设计的基于MEK受体的治疗有可能改善目前标准治疗（吉西他滨/放射）对这种疾病的疗效。该项目将提供独特的分子成像能力，以优化人类胰腺癌中基于MEK通道的联合治疗，并指导未来使用这种机制类药物的临床试验设计。

DESCRIPTION (provided by applicant): The RAS-MAP kinase signaling cascade is a key pathway that is activated in the vast majority of human pancreatic cancers. Among the multiple protein players critical to its biological output, the downstream kinase MEK, has emerged as an attractive candidate for pharmacologic inhibition. With the availability of a number of recently developed MEK specific agents, efforts need to be directed toward the design of a clinical trial wherein dosing and schedule have been optimized. The primary goal of this proposal is to systematically investigate MEK inhibition as a strategy for the treatment of pancreatic cancer using a novel imaging approach in preclinical models that have historically been difficult to study. A genetically engineered mouse model of pancreatic ductal adenocarcinoma will be modified by the introduction of reporters for MEK activity and for induction of apoptosis. Cre-dependent induction of these onboard molecular imaging reporters will enable bioluminescence imaging-based monitoring of tumor burden, targeted inhibition of MEK, and longitudinal treatment response in live animals as imaged by apoptosis induction. We hypothesize that MEK inhibitors will offer clear therapeutic benefit when integrated into currently adopted chemo- and radiotherapy regimens for the treatment of pancreatic cancer. However, the current paradigm involving chronic daily dosing that has become standard practice in drug clinical trials today will be evaluated here. Our molecular imaging approach will increase our understanding of the relationship between dynamics of target modulation and therapeutic outcome. Multiple doses and schedules will be evaluated to optimize treatment by comparing sustained versus maximal target inhibition. We believe this to be the first study undertaken to optimize MEK inhibitor treatment on the basis of bioluminescent imaging of pancreatic cancer originating and proliferating directly in the mouse pancreas. Additionally, a panel of primary orthotopic xenografts will be tested that will more likely reflect the heterogeneity encountered in clinical trials. The promise of diffusion-MRI as a surrogate biomarker of early therapeutic response will also be explored for future clinical translation. The use of novel imaging surrogates for key signaling events could have a major impact on the treatment of pancreatic cancer, facilitating an early assessment of patient response as well as accelerating trial timelines. We propose a paradigm shifting strategy for the rational design and optimization of clinical trials by integratig novel mouse models with imaging readouts of drug-target interaction. The net impact will provide for improved therapeutic outcomes in pancreatic cancer and serve as a prototype approach applicable to other targets and patient populations. PUBLIC HEALTH RELEVANCE: There is an urgent need to develop more effective therapies to improve the low survival rate for pancreatic cancer. Rationally designed MEK inhibitor-based therapies have the potential to improve the efficacy of current standard of care (gemcitabine/radiation) for this disease. This project will provide unique molecular imaging capabilities to optimize MEK inhibitor-based combination therapies in human pancreatic cancer and guide future clinical trial design with this mechanistic class of agents.