Novel Therapy to Inhibit IPMN Progression

摘要 胰腺导管腺癌(PDA)是一种5年生存率仅为10%的恶性胰腺癌。 因此，瞄准PDA前体是最优先的领域。其中最普遍和最容易的 具有PDA先兆的可识别高危个体是导管内乳头状黏液性肿瘤患者 (IPMN)。目前，对IPMN患者进行主动监测(AS)和手术治疗，以发展成高发病率。 有斑点的风险。FDA批准的防止进展为PDA的IPMN的非手术治疗并不存在。 开发有效的IPMN代理面临的挑战包括识别可以在人类身上进行测试的代理 临床试验，可以进入临床的一组适当的高危患者的可用性 预防试验，并确定可以预测化学预防药物疗效的潜在生物标记物。 我们团队最近的工作发现δ-生育三烯醇(DT3)是一种新型的IPMN凋亡诱导剂， MUC4作为IPMN进展的驱动因素和预测生物标记物，以及理想的激励队列 AS上的IPMN患者，这为解决这些高度优先的挑战提供了新的机会。在……里面 最近完成了一项由NCI赞助的第一阶段机会窗试验，我们观察到DT3是安全的和 显著诱导IPMN患者肿瘤细胞的凋亡。我们的初步研究也 提示MUC4的表达与DT3的应答有关。此外，我们观察到MUC4 在致癌KRAS背景下的表达导致了小鼠胰腺IPMN的发生。 因此，这一提议的总体假设是DT3将通过靶向阻止IPMN的进展 对IPMN前体病变的启动、维持和进展至关重要的通路。 这一假设将在两个目标中得到检验：在目标1中，我们将进行第二阶段的多机构、随机、 DT3预防IPMN进展的安慰剂对照试验(106名患者/组) 来自莫菲特癌症中心、内布拉斯加大学医学中心和梅奥诊所。主端点将 三年后根据国际指南标准获得IPMN无进展存活期。病人将会是 通过MRI/MRCP和内窥镜超声进行监测-基于护理标准。更进一步，相互关联 研究将利用放射组学以及组织和血清样本来研究反应和识别的生物标志物 DT3的作用机制。在目标2中，我们将定义DT3的分子靶点，其作用机制 在IPMN(KC-1)基因工程模型中，确定DT3的生物标志物 MUC4 TG)，包含致癌KRAS和可诱导的MUC4过表达的突变组合。 从AIM 2中的研究中获得的见解将通过从AIM 1中的患者那里获得的生物标本来验证。 这项多学科的提案将提供机会，通过提前 有望无创降低IPMN进展为PDA的风险并提供新的 对DT3促凋亡作用的分子机制的洞察。

ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is an incalcitrant malignancy with a 5-year survival of only 10%. Therefore, targeting PDA precursors is an area of the highest priority. Amongst the most prevalent and easily identifiable high-risk individuals with PDA precursors are patients with intraductal papillary mucinous neoplasm (IPMN). Currently, patients with IPMN are managed with active surveillance (AS) and surgery to develop high- risk stigmata. FDA-approved non-operative treatment of IPMN to prevent progression to PDA does not exist. Challenges to developing an effective IPMN agent include identifying agents that can be tested in human clinical trials, availability of an appropriate group of high-risk patients that can be entered into a clinical prevention trial, and identifying potential biomarkers that could predict the efficacy of chemoprevention agents. Recent work from our team has identified δ-tocotrienol (DT3) as a novel apoptosis-inducing agent for IPMN, MUC4 as a driver as well as a predictive biomarker of IPMN progression, and an ideal cohort of motivated patients with IPMN on AS, that provides new opportunities to address each of these high-priority challenges. In a recently completed NCI-sponsored Phase I window-of-opportunity trial, we observed that DT3 is safe and significantly induces apoptosis in the neoplastic cells of patients with IPMN. Our preliminary studies also suggest that MUC4 expression is associated with response to DT3. Further, we observed that MUC4 expression in the background of oncogenic KRAS results in the development of IPMN in mouse pancreas. Thus, the overall hypothesis for this proposal is that DT3 will block IPMN progression by targeting pathways that are crucial for the initiation, maintenance, and progression of IPMN precursor lesions. This hypothesis will be tested in two aims: In Aim 1, we will conduct a Phase II multi-institutional, randomized, placebo-controlled trial of DT3 in the prevention of IPMN progression (106 patients/arm) utilizing individuals from Moffitt Cancer Center, University of Nebraska Medical Center, and Mayo Clinic. The primary endpoint will be IPMN Progression-Free Survival based on international guidelines criteria after three years. Patients will be monitored with MRI/MRCP and endoscopic ultrasound-based on a standard of care. Further, correlative studies will utilize radiomics and tissue and serum samples to study the biomarkers of response and discern the mechanism of action of DT3. In Aim 2, we will define the molecular targets of DT3, the mechanism of biochemical responses, and identify biomarkers of DT3 in the genetically engineered model of IPMN (KC- MUC4 Tg) that harbors the mutational combination of oncogenic KRAS and inducible MUC4 overexpression. Insights gained from the studies in Aim 2 will be validated with biospecimens obtained from patients in Aim 1. This multidisciplinary proposal will allow opportunities to reduce PDA mortality by advancing a promising noninvasive paradigm for reducing the risk of IPMN progression to PDA and providing novel insights into the molecular mechanisms contributing to the pro-apoptotic effects of DT3.