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) 是一种顽固性恶性肿瘤，5 年生存率仅为 10%。 因此，针对 PDA 前体是最普遍且最容易的领域。 可识别的PDA前体高危个体是导管内乳头状粘液性肿瘤患者 (IPMN) 目前，IPMN 患者通过主动监测 (AS) 和手术进行治疗，以提高病情。 FDA 批准的 IPMN 预防进展为 PDA 的非手术治疗并不存在。 开发有效的 IPMN 药物面临的挑战包括确定可以在人体中进行测试的药物 临床试验、可进入临床试验的适当高风险患者组的可用性 预防试验，并确定可以预测化学预防药物功效的潜在生物标志物。 我们团队最近的工作已确定 δ-生育三烯酚 (DT3) 是 IPMN 的一种新型细胞凋亡诱导剂， MUC4 作为 IPMN 进展的驱动因素和预测生物标志物，是一个理想的动机群体 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。 最近完成的 NCI 赞助的第一期机会窗口试验中，我们观察到 DT3 是安全的，并且 我们的初步研究还显着诱导 IPMN 患者的肿瘤细胞凋亡。 此外，我们观察到MUC4 致癌 KRAS 背景下的表达导致小鼠胰腺中 IPMN 的形成。 因此，该提案的总体假设是 DT3 将通过靶向阻止 IPMN 进展 对 IPMN 病变的发生、维持和进展至关重要的途径。 该假设将在两个目标中进行检验：在目标 1 中，我们将进行 II 期多机构、随机、 使用个体进行 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的主要终点将。 根据国际指南标准，患者三年后将获得 IPMN 无进展生存期。 根据护理标准，使用 MRI/MRCP 和内窥镜超声进行监测。 研究将利用放射组学、组织和血清样本来研究反应的生物标志物并辨别 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。 生化反应，并在 IPMN 基因工程模型（KC- MUC4 Tg) 包含致癌 KRAS 和诱导性 MUC4 过表达的突变组合。 从目标 2 的研究中获得的见解将通过从目标 1 的患者获得的生物样本进行验证。 这项多学科提案将通过推进 非侵入性范例，用于降低有希望的 IPMN 进展为 PDA 的风险，并提供新的 深入了解 DT3 促凋亡作用的分子机制。