Project 2: Building Combinatorial Therapies against KRAS-mutant Colorectal and Pancreatic Cancer

摘要 在约90%的胰腺癌（PDAC）和约50%的结直肠癌（CRC）中发现了KRAS基因的激活突变。 癌的然而，设计用于对抗或消除KRAS信号传导的治疗策略仍然存在。 不成功。冗余的信号通路和复杂的实体瘤微环境是肿瘤生长的关键障碍。 目前的KRAS目标定位工作。大多数针对KRAS的常规药物测试通常使用常规的 细胞系系统缺乏临床相关性和生物学异质性，从而在患者中失败。更 最近，患者来源的模型，包括原代细胞培养物、类器官或球状体，已被部署在 大屏幕设计，以确定有效的组合方案。由于患者衍生模型在临床上 代表性的先导单一试剂或组合显示出更高的转化成功可能性。我们 一种方法的长期目标是建立和测试使用患者来源的异种移植物（PDX）与一种 更有效地测试药物敏感性的离体肿瘤组织培养测定。使用这种离体方法，我们测试了 针对一组10种PDAC PDX肿瘤的36种药物组合，以鉴定证明 协同效应这些组合包括MEK抑制剂沿着多激酶抑制剂、suntinib或 CDK 4/6抑制剂。使用MEK-CDK 4/6组合的协同抗癌活性也发生在我们的CRC PDX中 已经转化为正在进行的临床试验的模型。我们的初步研究和正在进行的临床试验提供了 在大的PDX队列中进一步测试这些组合的强有力的理由。在拟议的研究中，我们的目标是： 1)通过体内PDX试验确定基于MEK受体的组合的有效性; 2） 建立和表征来自参加MEK和CDK 4/6组合的临床试验的患者的PDX 抑制剂;和3）鉴定响应肿瘤的生物标志物并探索耐药机制。 在使用临床相关患者衍生模型系统的研究中识别电极导线组合预测 在未来的临床研究中获得成功的可能性更高。此外，所有拟定的试验试剂均已批准使用 或正在临床试验中进行评估。因此，这些努力很有可能将 快速转化为临床，迅速造福PDAC和CRC患者。

Abstract Activating mutations of the KRAS gene are found in ~90% of pancreatic (PDAC) and ~50% of colorectal (CRC) cancers. However, therapeutic strategies designed to counter or extinguish KRAS signaling remain unsuccessful. Redundant signaling pathways and a complex solid tumor microenvironment are key barriers to current KRAS targeting efforts. Most conventional drug testing targeting KRAS has commonly used conventional cell line systems that lack clinical relevance and biological heterogeneity and thereby failed in patients. More recently, patient-derived models, including primary cell cultures, organoids or spheroids have been deployed in large screens designed to identify effective combination regimens. Since patient-derived models more clinically representative, lead single agents or combinations are exhibiting a higher likelihood of translational success. Our approach long-term goal is to establish and test agents using patient-derived xenografts (PDX) coupled with an ex-vivo tumor tissue culture assay that more effectively tests drug sensitivity. Using this ex-vivo method we tested 36 drug combinations against a panel of 10 PDAC PDX tumors to identify drug combinations that demonstrate synergistic effects. These combinations include, MEK inhibitors along with multi-kinase inhibitor, suntinib, or CDK4/6 inhibitors. Synergistic anticancer activity using MEK-CDK4/6 combinations also occurs in our CRC PDX models that have translated to an ongoing clinical trial. Our preliminary studies and ongoing clinical trial provide a strong rationale to further test these combinations in large cohorts of PDXs. In the proposed study, we aim to: 1) determine the effectiveness of the MEK inhibitor-based combinations through in vivo PDX trials; 2) establish and characterize PDXs from patients enrolled in a clinical trial that combines MEK and CDK4/6 inhibitors; and 3) identify biomarkers of responding tumors and explore the mechanisms of resistance. The identification of lead combinations in studies using clinically relevant patient-derived model systems predicts a higher chance of success in future clinical studies. In addition, all proposed test agents are approved for use against cancer or are being evaluated in the clinical trials. Thus, there is a high probability that these efforts will be quickly translated to the clinic and rapidly benefit PDAC and CRC patients.