Dual checkpoint blockade for the treatment of KRAS- or BRAF-driven neoplastic disease

双检查点阻断治疗 KRAS 或 BRAF 驱动的肿瘤疾病

• 批准号: 289354784
• 负责人: Professor Dr. Christian Reinhardt
• 金额: --
• 依托单位: Klinik für Hämatologie und Stammzelltransplantation
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/289354784?language=en
• 关键词: Dual; checkpoint; blockade; treatment; KRAS

KRAS is one of the most frequently mutated genes in human cancer. As direct targeting of KRAS is difficult, indirect approaches have been proposed. These regimens have shown promising preclinical activity and multiple clinical trials are underway, but the clinical feasibility and validity has yet to be demonstrated.Our own preliminary data show that KRAS-driven tumors display a non-oncogene addiction to functional cell cycle checkpoint signaling through Chk1 and MK2. Our approach thus substantially differs from most previous strategies, developed to treat KRAS-mutant cancers, which typically target KRAS or one of its direct downstream signaling effectors, in order to abolish its oncogenic potential. However, many questions regarding this novel synthetic lethal interaction remain unanswered and currently preclude further validation in the clinic. For instance: Are other checkpoint kinases, such as ATM or Chk2 equally good targets for checkpoint-abrogating therapeutic regimens? This question is particularly important, as Chk1 knockout mice display embryonic lethality, which might suggest that long-term treatment with Chk1 inhibitors might be limited by toxicity. Do other KRAS- or BRAF-driven malignancies, such as colorectal cancer display similar sensitivity against Chk1- and MK2-inhibitors? Could immuno-histochemistry-based biomarkers be established that allow an accurate prediction of cell cycle checkpoint dependence? To address these questions and to facilitate a clinical translation of our novel treatment regimen, we propose three specific aims in this application:Aim 1: Validate oncogenic KRAS and BRAF mutations as predictors for non-oncogene addiction to cell cycle checkpoint signalingAim 2: Assess whether Chk2- or ATM-inhibitors are equally effective combination partners as Chk1-inhibitorsAim 3: Establish immunohistochemistry-based biomarkers to predict non-oncogene addiction to cell cycle checkpoint signalingThese aims specifically test the hypothesis that 1) KRAS and BRAF are generalizable predictors of cell cycle checkpoint addiction, independent of the cancer entity, 2) ATM- and Chk2 kinase inhibitors can substitute Chk1 inhibitors in the cell cycle checkpoint-abrogation regimen and 3) that in addition to DNA sequencing-based response prediction, immunohistochemistry-based scoring systems can be established that accurately predict response to cell cycle checkpoint-abrogating therapeutic regimens. Answering these questions in relevant, autochthonous mouse models and human material will pave the way for a rapid clinical validation of our hypothesis.

KRAS是人类癌症中最常见的突变基因之一。由于KRAS的直接靶向是困难的，已经提出了间接的方法。这些方案已经显示出有希望的临床前活性，多项临床试验正在进行中，但临床可行性和有效性尚未得到证明。我们自己的初步数据显示，KRAS驱动的肿瘤显示出对功能性细胞周期检查点信号的非癌基因成瘾，通过Chk 1和MK2。因此，我们的方法与大多数以前的治疗KRAS突变型癌症的策略有很大不同，这些策略通常针对KRAS或其直接下游信号效应子之一，以消除其致癌潜力。然而，关于这种新的合成致死相互作用的许多问题仍然没有答案，目前排除在临床上进一步验证。例如：其他检查点激酶，如ATM或Chk 2，是否也是取消检查点治疗方案的良好靶点？这个问题特别重要，因为Chk 1基因敲除小鼠显示胚胎致死性，这可能表明Chk 1抑制剂的长期治疗可能受到毒性的限制。其他KRAS或BRAF驱动的恶性肿瘤，如结直肠癌，对Chk 1和MK2抑制剂是否表现出相似的敏感性？是否可以建立基于免疫组织化学的生物标志物，从而准确预测细胞周期检查点依赖性？为了解决这些问题并促进我们的新型治疗方案的临床转化，我们在本申请中提出了三个具体目标：目标1：将致癌KRAS和BRAF突变作为非癌基因对细胞周期检查点信号成瘾的预测因子目标2：评估Chk 2-或ATM-抑制剂是否是与Chk 1-抑制剂同样有效的组合伴侣目标3：建立基于生物化学的生物标志物来预测非癌基因对细胞周期检查点信号的成瘾这些目标具体地测试了以下假设：1）KRAS和BRAF是细胞周期检查点成瘾的可推广的预测因子，独立于癌症实体，2）ATM和Chk 2激酶抑制剂可以在细胞周期检查点废除方案中取代Chk 1抑制剂，3）除了基于DNA测序的反应预测外，还可以建立基于细胞化学的评分系统，准确预测对细胞周期检查点废除治疗方案的反应。在相关的、本土的小鼠模型和人体材料中研究这些问题将为我们的假设的快速临床验证铺平道路。