Project 3: Transcriptomic subtypes, response predictions, and therapy selection

项目3：摘要 FOLFIRINOX和吉西他滨+nab-紫杉醇（GNP）已成为患者的一线治疗 转移性胰腺癌（PDAC）这两种方案尚未在一线进行比较 设置和治疗选择由医生选择指导。在转移性PDAC患者中， 对于一线FOLFIRINOX无应答的患者，相当大比例的患者将对二线GNP产生稳健应答。 这强烈表明，可能有一部分患者可能对以下药物有显著的临床反应： GNP而非FOLFIRINOX。将患者与最有效的一线治疗相匹配是一项关键而未得到满足的 需要的 我们已经确定了PDAC的分子亚型是强大的和可复制的。两项临床试验的分析 已经表明基础亚型对基于FOLFIRINOX的治疗没有反应，并强调了 迫切需要确定替代治疗方法。最近的研究结果表明，基底部肿瘤患者 与FOLFIRINOX相比，对GNP的反应更好。根据我们对亚型相关治疗的发现， 作为回应，我们开发了一个强大的和可复制的单样本分类器（PurIST），现在是CLIA批准的 分析，并将使用此建议，以前瞻性地评估是否可以使用的PurIST分类器， 直接治疗选择。 利用位于查佩尔山的北卡罗来纳州大学的分子分型专业知识， 我们利用威斯康星州医学院胰腺癌项目庞大的临床基础设施 提出一项临床试验，其中PurIST亚型将用于指导初始化疗。对我们 这将是第一个使用分子分型来指导新辅助治疗的试验。 这项试验的结果将证明精确的肿瘤学方法，如PurIST，是否有助于指导 治疗并改善可能对FOLFIRINOX或 GnP。 与此同时，我们将确定肿瘤和肿瘤微环境的特定特征是否可以预测 通过尖端试验的创新计算方法对不同疗法的反应。最后， 通过我们新的蛋白质组学方法，我们发现基底肿瘤具有不同的激酶谱。我们 显示激酶抑制剂在PDAC中的有效性可能被忽视，因为约20%的PDAC患者 是基础的，亚型特异性激酶可能是有前途的目标。

PROJECT 3: ABSTRACT FOLFIRINOX and gemcitabine plus nab-paclitaxel (GnP) have emerged as the first-line treatment for patients with metastatic pancreatic cancer (PDAC). These two regimens have not been compared in the first-line setting, and treatment selection is guided by physician choice. Among patients with metastatic PDAC who do not respond to first-line FOLFIRINOX, a substantial proportion will have a robust response to second-line GnP. This strongly suggests that there may be a subset of patients who may have significant clinical response to GnP but not FOLFIRINOX. Matching patients to the most effective first-line therapy is a critical and unmet need. We have identified molecular subtypes of PDAC that are robust and replicable. Analysis from two clinical trials has shown that the basal subtype does not respond to FOLFIRINOX-based therapies and emphasizes the critical need to identify alternative treatments. Recent results have shown that patients with basal tumors are more responsive to GnP compared to FOLFIRINOX. Based on our findings of subtype associated treatment response, we developed a robust and replicable single-sample classifier (PurIST) that is now a CLIA-approved assay, and will be used this proposal to prospectively evaluate whether the PurIST classifier can be used to direct treatment selection. Leveraging the strength of molecular subtyping expertise at the University of North Carolina at Chapel Hill and the tremendous clinical infrastructure at the Medical College of Wisconsin’s Pancreatic Cancer Program, we propose a clinical trial where PurIST subtyping will be used to direct the initial chemotherapy. To our knowledge this will be the first trial to use molecular subtyping to direct treatment in the neoadjuvant setting. Results from this trial will demonstrate if precision oncology approaches such as PurIST may help direct treatment and improve outcome for patients that may otherwise be less responsive to either FOLFIRINOX or GnP. In parallel, we will determine if specific characteristics in the tumor and tumor microenvironment may predict response to different therapies through innovative computational approaches of cutting edge trials. Finally, through our novel proteomic approaches we have found that basal tumors have differential kinase profiles. We show that effectiveness of kinases inhibitors in PDAC may have been overlooked as ~20% of PDAC patients are basal, and that subtype-specific kinases may be promising targets.