Co-Targeting CDK4 and MEK for Metastatic Colorectal Cancer Therapy

 描述(申请人提供)：在广泛的人类癌症中，KRAS异常过度激活在肿瘤的发生和发展中起着重要作用。KRAS基因突变在结直肠癌中的发生率尤其高，其发生率为40%。我们假设CDK4和MEK的双重靶向将为肿瘤对MEK信号上瘾的结直肠癌患者亚群提供明显的治疗益处。这项提案的首要目标是产生令人信服的临床前支持，为合理设计基于CDK4/MEK抑制剂的联合疗法治疗转移性结直肠癌患者的临床试验提供信息。该项目成功的关键是纳入可预测临床疾病的临床前动物模型。因此，我们建议研究一组原始的人类异种移植模型，这些模型是从我们研究所进行的手术中获得的标本建立的，试图总结在结直肠癌患者群体中遇到的异质性。所有模型都将从分子水平分析与结直肠癌进展有关的基因组异常，包括对KRAS和RB的分析。使用分别对CDK4/6和MEK具有高度选择性的临床候选药物帕博西利(PD0332991)和临床批准的曲美替尼，我们建议对我们整个Rb+异种移植队列进行药理学分析，以确定对这两种单一药物都有反应的模型亚群。针对这类被认为对CDK4/MEK联合靶向策略有最高反应的模型子集，我们建议使用分子成像方法来设计这两种药物的最佳组合方案。我们的原代人类结直肠癌模型将转导Luc2-IRES-mCherry慢病毒，以便在盲肠内原位植入后，能够对播散性疾病引起的肝脏病变进行生物发光成像。当我们比较同时给药策略和顺序给药策略的治疗结果时，将评估多个剂量和时间表。我们相信，这是第一项基于直接在小鼠肝脏起源和增殖的转移病变的生物发光成像的基础上，优化CDK4和MEK的联合靶向治疗结直肠癌的研究。

 DESCRIPTION (provided by applicant): Aberrant hyperactivation of KRAS plays a prominent role in tumor initiation and progression in a broad spectrum of human cancers. The incidence of KRAS mutations is especially high in colorectal malignancies, where it occurs at a frequency of >40%. We hypothesize that dual targeting of CDK4 and MEK will offer clear therapeutic benefit for the subpopulation of colorectal patients whose tumors are addicted to MEK signaling. The overarching goal of this proposal is to generate compelling preclinical support to inform rationally designed clinical trials of CDK4/MEK inhibitor-based combination therapies for metastatic colorectal cancer patients. Critical to the success of this project will be incorporatio of preclinical animal models that are predictive of clinical disease. Therefore, we propose to study a panel of primary human xenograft models established from specimens procured from surgeries carried out at our Institution in an attempt to recapitulate the heterogeneity encountered in the CRC patient population. All models will be molecularly profiled for genomic aberrations implicated in colorectal cancer progression, including analysis of KRAS and RB. Using the clinical candidate palbociclib (PD0332991) and clinically approved trametinib, which are highly selective for CDK4/6 and MEK, respectively, we propose to carry out pharmacologic profiling of our entire cohort of RB+ xenografts to identify the subpopulation of models that are responsive to both single agents. Focusing on this subset of models judged to have the highest likelihood of responding to a CDK4/MEK co-targeting strategy, we propose to employ a molecular imaging approach to design the optimal combination regimen for these two agents. Our primary human CRC models will be transduced with Luc2-IRES-mCherry lentivirus to enable bioluminescent imaging of liver lesions resulting from disseminated disease after orthotopic implantation into the cecum. Multiple doses and schedules will be evaluated as we compare therapeutic outcome of concurrent versus sequential dosing strategies. We believe this to be the first study undertaken to optimize co-targeting of CDK4 and MEK to treat colorectal cancer on the basis of bioluminescent imaging of metastatic lesions originating and proliferating directly in the mouse liver.