Tailoring Therapy to Pancreatic Cancer Subtypes

背景：胰腺导管腺癌(PDA)是最致命的癌症之一。这个项目规划了 新的、基于亚型的PDA治疗方法。我们知道，KRAS突变导致了大约90%的PDA， 但由于我们不能直接抑制KRAS，我们用非常有效的化疗组合来治疗PDA 患者难以忍受，对KRAS置之不理。我们在这里的方法集中在PDA的使用上 我们发现的指导PDA中MEK抑制剂组合的亚型。我们在这里将重点放在经典 (C)-和准间充质(QM)-PDA亚型，加起来约占所有PDA患者的75%。 理论基础：PDA亚型使个性化的PDA治疗成为可能，因为亚型可以预测治疗反应。 此外，PDA亚型不同，逃避MEK抑制剂的机制(S)也不同。C-PDA显示强劲 通过受体酪氨酸激酶和非典型蛋白激酶C信号的反弹信号。相比之下，我们 我发现了一种新的KRAS驱动的通路，导致了QM-PDA中LIF的病理性表达 亚型，导致STAT3信号水平升高和致癌。重要的是，这两条路径都可以 有针对性，但应在不同的PDA亚型中单独进行。 方法：我们将使用体内临床前PDA模型来优化MEK和ERK抑制剂的组合 每个亚型都有不同的合理组合。在QM-PDA子类型中，我们将耗尽LIF信令 同时接受吉西他滨治疗。在C-PDA亚型中，我们将比较抑制策略 具有MEK抑制作用的蛋白激酶C。最后，我们还将使用公正的方法对体内MEK进行讯问 在两个亚型中使用创新的、饱和的RAS途径和 癌细胞中的微环境相互作用路径，在完整的有机体中模拟。 预期结果：从R01产生的结果将既定义智力大纲，也定义实用， 掌上电脑个性化护理的组织原则。启动基因组定义的PDA亚型的临床试验 这笔赠款的预期交付以及了解MEK抑制剂的反应和耐药性是另一个原因。 影响：该项目100%与胰腺癌相关。我们的建议开创了新的方法 通过使用多种疾病及其突出亚型的互补模型进行PDA治疗。

Background: Pancreatic Ductal Adenocarcinoma (PDA) is among the deadliest of cancers. This project lays out new, subtype-based treatment approaches to PDA. We know that KRAS mutation drives around 90% of PDA, but since we cannot directly inhibit KRAS, we treat PDA with combinations of chemotherapies that are very difficult for patients to tolerate, and leave KRAS unaddressed. Our approach here centers on the use of PDA subtypes that we discovered to guide MEK inhibitor combinations in PDA. We will focus here on the Classical (C)- and Quasi-Mesenchymal (QM)-PDA subtypes, which together represent ~75% of all PDA patients. Rationale: PDA subtypes enable personalized PDA therapy because subtype predicts response to therapy. Furthermore, the mechanism(s) of escape from MEK inhibitors differ by PDA subtype. C-PDA displays robust rebound signaling through receptor tyrosine kinase and atypical protein kinase C signaling. By contrast, we have discovered a new KRAS-driven pathway resulting in the pathological expression of LIF, in the QM-PDA subtype, resulting in elevated and cancer-driving levels of STAT3 signaling. Importantly, both pathways can be targeted, but should be pursued separately in distinct PDA subtypes. Methods: We will use in vivo preclinical PDA models to optimize MEK and ERK inhibitor combinations using distinct, rational combinations for each subtype. In the QM-PDA subtype, we will deplete LIF signaling alongside concurrent gemcitabine treatment. In the C-PDA subtype, we will compare strategies inhibiting protein kinase C with MEK inhibition. Finally, we will also use unbiased methods to interrogate in vivo MEK inhibitor resistance pathways in both subtypes using an innovative, saturating assessment of RAS pathway and microenvironmental interacting pathways in cancer cells, modeled in the intact organism. Expected Results: Results emanating from this R01 will define both the intellectual outline as well as practical, organizing principles to personalize care in PDA. Initiating clinical trials in genomically defined PDA subtypes is an expected deliverable of this grant and understanding MEK inhibitor response and resistance is another. Impact: This project is 100% relevant to pancreatic adenocarcinoma. Our proposal pioneers new approaches to PDA treatment through a use of multiple complementary models of the disease and its prominent subtypes.