Novel Therapy to Inhibit IPMN Progression

抑制 IPMN 进展的新疗法

• 批准号: 10446455
• 负责人: Surinder K. Batra
• 金额: $ 68.62万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-08 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446455
• 关键词: Abdomen; Address; Animal Model; Apoptosis; Apoptotic; Area; Biochemical; Biological Availability; Biological Markers; Cancer Center; Cell Line; Cell Proliferation; Cells; Cessation of life; Chemopreventive Agent; Clinic; Clinical; Clinical Trials; Complex; Consensus; Correlative Study; Data; Development; Diagnosis; Endoscopic Ultrasonography; FDA approved; Genetic Engineering; Genetically Engineered Mouse; Goals; Guidelines; Human; Immune; Individual; Infiltration; International; KRAS oncogenesis; KRAS2 gene; Lesion; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Medical; Medical center; Micronutrients; Modeling; Molecular; Molecular Target; Monitor; Mucinous Neoplasm; Mucins; Mus; Mutation; Nebraska; Normal tissue morphology; Oncogenic; Operative Surgical Procedures; Oral; Organoids; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Papillary; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiological; Prevention; Prevention trial; Progression-Free Survivals; Regulation; Resistance; Risk; Safety; Sampling; Serum; Signal Transduction; Study of serum; Testing; Therapeutic; Tissues; United States; Universities; Woman; Work; arm; base; biomarker discovery; cancer cell; cohort; delta tocotrienol; driver mutation; drug development; druggable target; early phase trial; effectiveness evaluation; glycosylation; high risk; high risk population; imaging study; insight; men; mortality; mouse model; multidisciplinary; multiple omics; neoplasm therapy; neoplastic cell; novel; novel therapeutics; overexpression; pancreas development; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; phase 1 study; phase I trial; potential biomarker; predicting response; predictive marker; prevent; primary endpoint; radiomics; randomized placebo controlled trial; response; response biomarker; risk stratification; standard of care; therapy development; treatment duration; treatment response; trial design; tumor; tumor growth; tumor progression

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.

抽象的 胰腺导管腺癌（PDA）是一种不症状恶性肿瘤，仅5年生存率仅为10％。 因此，靶向PDA前体是优先级最高的领域。在最普遍，最容易的 具有PDA前体的可识别高危个体是导管内乳头状粘液肿瘤的患者 （IPMN）。目前，IPMN患者进行了主动监测（AS）和手术的治疗 风险污名。不存在FDA批准的IPMN的非手术治疗，以防止进展为PDA。 开发有效IPMN代理的挑战包括识别可以在人类中测试的代理 临床试验，可以进入临床的适当的高风险患者的可用性 预防试验，并确定可以预测化学预防剂效率的潜在生物标志物。 我们团队的最新工作已经确定δ-苯酚（DT3）是一种新型凋亡诱导的IPMN剂， MUC4作为驱动器以及IPMN进展的预测生物标志物，以及理想的融合队列 IPMN AS的患者提供了新的机会来应对这些高优先挑战的挑战。在 最近完成的NCI发起的第一阶段的大型运动窗口试验，我们观察到DT3是安全的，并且 显着诱导IPMN患者的肿瘤细胞凋亡。我们的初步研究 表明MUC4表达与对DT3的响应有关。此外，我们观察到MUC4 在致癌性KRAS的背景下的表达导致小鼠胰腺中IPMN的发展。 这是该提案的总体假设是DT3将通过靶向IPMN的进展 对于IPMN前体病变的主动，维持和进展至关重要的途径。 该假设将以两个目的进行检验：在AIM 1中，我们将进行II期多机构，随机，随机， DT3的安慰剂对照试验使用个体预防IPMN进展（106名患者） 来自莫菲特癌症中心，内布拉斯加州大学医学中心和梅奥诊所。主要终点将 三年后，根据国际准则标准，根据国际准则标准成为IPMN无进展生存。患者会 根据MRI/MRCP和基于内窥镜超声检查的护理监测。此外，相关 研究将利用放射组学，组织和血清样品研究反应的生物标志物和辨别 DT3的作用机理。在AIM 2中，我们将定义DT3的分子靶标的机理 生化反应，并在IPMN的一般工程模型中识别DT3的生物标志物（KC- MUC4 tg）具有致癌性KRAS和诱导MUC4过表达的突变组合。 AIM 2中从研究中获得的见解将通过AIM 1中的患者获得的生物测量来验证。 这项多学科的建议将使机会通过推进一个 有望降低IPMN发展为PDA并提供新颖的无创范式 洞悉导致DT3促凋亡作用的分子机制。