Design of MEK Inhibitor Regimens for the Treatment of Pancreatic Cancer

描述(申请人提供)：RAS-MAP激酶信号级联是在绝大多数人胰腺癌中被激活的关键途径。在对其生物输出至关重要的多种蛋白质中，下游的激酶MEK已成为一种有吸引力的药物抑制候选蛋白。随着大量新近开发的MEK特异性药物的问世，需要努力设计一种临床试验，其中剂量和时间表都得到了优化。这项建议的主要目标是系统地研究MEK抑制作为治疗胰腺癌的策略，在历史上难以研究的临床前模型中使用一种新的成像方法。通过引入MEK活性和诱导细胞凋亡的报告，将对胰腺导管腺癌的基因工程小鼠模型进行修改。依赖于Cre的这些机载分子成像报告的诱导将使基于生物发光成像的肿瘤负荷监测、MEK的靶向抑制以及通过细胞凋亡诱导成像的活体动物的纵向治疗反应成为可能。我们假设，当MEK抑制剂与目前采用的化疗和放射治疗方案相结合治疗胰腺癌时，将提供明显的治疗益处。然而，目前涉及慢性每日剂量的范例已经成为当今药物临床试验的标准做法，它将 在这里接受评估。我们的分子成像方法将增加我们对靶点调节动力学和治疗结果之间关系的理解。将通过比较持续和最大靶向抑制来评估多剂量和多方案以优化治疗。我们相信这是第一次在生物发光成像的基础上对直接在小鼠胰腺起源和增殖的胰腺癌进行优化MEK抑制剂治疗的研究。此外，将对一组主要的原位异种移植物进行测试，这将更有可能反映临床试验中遇到的异质性。弥散磁共振成像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。关键信号事件的新型成像替代物的使用可能会对胰腺癌的治疗产生重大影响，有助于及早评估患者的反应，并加快试验时间表。我们提出了一种范式转换策略，通过将新的小鼠模型与药物-靶标相互作用的成像读数相结合，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群体的原型方法。

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.