Novel Therapy to Inhibit IPMN Progression

抑制 IPMN 进展的新疗法

基本信息

  • 批准号:
    10446455
  • 负责人:
  • 金额:
    $ 68.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
摘要 胰腺导管腺癌是一种难以治愈的恶性肿瘤,5年生存率仅为10%。 因此,针对PDA前体是一个最高优先领域。在最普遍和最容易 导管内乳头状粘液性肿瘤是PDA前体的可识别高危个体 (IPMN)。目前,IPMN患者通过主动监测(AS)和手术进行管理,以发展高血压。 风险的烙印。FDA批准的非手术治疗IPMN以防止进展为PDA并不存在。 开发有效的IPMN试剂的挑战包括鉴定可以在人类中测试的试剂 临床试验,可进入临床试验的适当高风险患者群体的可用性 预防试验,并确定潜在的生物标志物,可以预测化学预防剂的疗效。 我们团队最近的工作已经确定δ-生育三烯酚(DT 3)是一种新的诱导IPMN的药物, MUC 4作为IPMN进展的驱动因素以及预测生物标志物,并且是一个理想的受动机的队列。 患者IPMN AS,这提供了新的机会,以解决这些高优先级的挑战。在 在最近完成的一项由NCI赞助的I期机会窗口试验中,我们观察到DT 3是安全的, 显著诱导IPMN患者的肿瘤细胞凋亡。我们的初步研究还 提示MUC 4表达与对DT 3应答相关。此外,我们观察到MUC 4 在致癌KRAS背景下的表达导致小鼠胰腺中IPMN的发展。 因此,该提议的总体假设是DT 3将通过靶向 这些通路对于IPMN前体病变的起始、维持和进展至关重要。 这一假设将在两个目标中进行检验:在目标1中,我们将进行一项II期多机构,随机, DT 3预防IPMN进展的安慰剂对照试验(106例患者/组),使用个体 来自莫菲特癌症中心、内布拉斯加大学医学中心和马约诊所。主要终点将 根据国际指南标准,3年后的IPMN无进展生存期。患者将 通过MRI/MRCP和内镜超声进行监测-基于标准护理。此外,相关 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, DT 3的作用机制。在目标2中,我们将定义DT 3的分子靶点, 生物化学反应,并在IPMN的基因工程模型中鉴定DT 3的生物标志物(KC- MUC 4 Tg),其具有致癌KRAS和诱导型MUC 4过表达的突变组合。 从目标2中的研究中获得的见解将通过目标1中患者的生物标本进行验证。 这一多学科的建议将有机会通过提高动脉导管未闭的死亡率, 有希望的非侵入性范例,用于降低IPMN进展为PDA的风险,并提供新的 深入了解有助于DT 3促凋亡作用的分子机制。

项目成果

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Surinder K. Batra其他文献

Functions of tumorigenic and migrating cancer progenitor cells in cancer progression and metastasis and their therapeutic implications
  • DOI:
    10.1007/s10555-007-9052-4
  • 发表时间:
    2007-02-02
  • 期刊:
  • 影响因子:
    8.700
  • 作者:
    Murielle Mimeault;Surinder K. Batra
  • 通讯作者:
    Surinder K. Batra
Wolfram 症候群の実態調査
关于 Wolfram 综合征的事实调查
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yukihiro Tamura;Michiyo Higashi;Sho Kitamoto;Seiya Yokoyama;Masahiko Osako;Michiko Horinouchi;Takeshi Shimizu;Mineo Tabata;Surinder K. Batra;Masamichi Goto;Suguru Yonezawa;松永仁恵,田部勝也,太田康晴,奥屋 茂,和田安彦,山田祐一郎,雨宮 伸,杉原茂孝,岡 芳知,谷澤幸生
  • 通讯作者:
    松永仁恵,田部勝也,太田康晴,奥屋 茂,和田安彦,山田祐一郎,雨宮 伸,杉原茂孝,岡 芳知,谷澤幸生
PP01.05 Targeting MUC16-Mediated KRASi Resistance in NSCLC
PP01.05 针对非小细胞肺癌中 MUC16 介导的 KRASi 耐药性
  • DOI:
    10.1016/j.jtho.2025.03.013
  • 发表时间:
    2025-04-01
  • 期刊:
  • 影响因子:
    20.800
  • 作者:
    Ashu Shah;Shamema Salam;Sanjib Chaudhary;Iniyan A. Muthamil;Imayavaramban Lakshmanan;Surinder K. Batra;Apar K. Ganti
  • 通讯作者:
    Apar K. Ganti
Mo1138 COMPARATIVE PROTEOMICS REVEALS TRANSLATIONAL POTENTIAL OF TARGETS FOR PANCREATIC DUCTAL ADENOCARCINOMA
  • DOI:
    10.1016/s0016-5085(23)02780-4
  • 发表时间:
    2023-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Mathilde Resell;Hanne-Line Rabben;Manoj Amrutkar;Lars Hagen;Surinder K. Batra;Caroline S. Verbeke;Timothy C. Wang;Duan Chen;Chun-Mei Zhao
  • 通讯作者:
    Chun-Mei Zhao
MUC5AC in stromal heterogeneity and the Progression of Pancreatic Cancer
  • DOI:
    10.1016/j.canlet.2023.216541
  • 发表时间:
    2024-01-28
  • 期刊:
  • 影响因子:
  • 作者:
    Surinder K. Batra
  • 通讯作者:
    Surinder K. Batra

Surinder K. Batra的其他文献

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{{ truncateString('Surinder K. Batra', 18)}}的其他基金

Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer
截短的O-聚糖依赖性机制诱导胰腺癌转移扩散
  • 批准号:
    10683305
  • 财政年份:
    2022
  • 资助金额:
    $ 68.62万
  • 项目类别:
Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer
用于胰腺癌光学手术导航的分子成像探针
  • 批准号:
    10557180
  • 财政年份:
    2022
  • 资助金额:
    $ 68.62万
  • 项目类别:
Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer
用于胰腺癌光学手术导航的分子成像探针
  • 批准号:
    10367553
  • 财政年份:
    2022
  • 资助金额:
    $ 68.62万
  • 项目类别:
Novel Therapy to Inhibit IPMN Progression
抑制 IPMN 进展的新疗法
  • 批准号:
    10640955
  • 财政年份:
    2022
  • 资助金额:
    $ 68.62万
  • 项目类别:
Connectivity mapping identified novel combination therapy for glioblastoma
连接映射确定了胶质母细胞瘤的新型联合疗法
  • 批准号:
    10504826
  • 财政年份:
    2022
  • 资助金额:
    $ 68.62万
  • 项目类别:
Connectivity mapping identified novel combination therapy for glioblastoma
连接映射确定了胶质母细胞瘤的新型联合疗法
  • 批准号:
    10686268
  • 财政年份:
    2022
  • 资助金额:
    $ 68.62万
  • 项目类别:
Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer
截短的O-聚糖依赖性机制诱导胰腺癌转移扩散
  • 批准号:
    10503433
  • 财政年份:
    2022
  • 资助金额:
    $ 68.62万
  • 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
  • 批准号:
    10156494
  • 财政年份:
    2021
  • 资助金额:
    $ 68.62万
  • 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
  • 批准号:
    10339431
  • 财政年份:
    2021
  • 资助金额:
    $ 68.62万
  • 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
  • 批准号:
    10551280
  • 财政年份:
    2021
  • 资助金额:
    $ 68.62万
  • 项目类别:

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