ON THE TRAIL TO PANCREAS CANCER-SELECTIVE TUMOR CELL DEATH (APOPTOSIS)

胰腺癌选择性肿瘤细胞死亡（细胞凋亡）的过程

• 批准号: 8054415
• 负责人: WILLIAM G HAWKINS
• 金额: $ 19.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054415
• 关键词: Animals; Apoptosis; Apoptotic; Biopsy; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Death; Cells; Clinical; Clinical Trials; Disease Management; Epitopes; Exhibits; Goals; Human; In Vitro; Incidence; Ligands; Link; Literature; Malignant neoplasm of pancreas; Modeling; Modification; Molecular Biology; Mus; NR4A1 gene; Patients; Radiation; Recombinants; Research Personnel; Resected; Role; Specificity; Survival Rate; TNF-related apoptosis-inducing ligand; TNFSF10 gene; Technology; Therapeutic; Time; Toxic effect; Translating; Treatment Protocols; Tumor Antigens; Tumor Tissue; United States; Work; base; cancer therapy; evidence base; experience; gemcitabine; improved; in vivo; innovation; mesothelin; mortality; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; pancreatic cancer cells; pancreatic neoplasm; patient population; pre-clinical; preclinical efficacy; preclinical safety; public health relevance; receptor; standard of care; tumor

DESCRIPTION (provided by applicant): On the TRAIL to Pancreas Cancer-Selective Cell Death (Apoptosis) Introduction: Pancreas cancer was the fourth leading cause of cancer-related mortality in the United States in 2008. There has been little progress in the management of this disease and the annual mortality rate remains nearly identical to the annual incidence rate. Novel therapeutic strategies are desperately needed. TNF-related apoptosis-inducing ligand (TRAIL, Apo2L) exhibits potent, selective apoptotic activity against tumors and is currently under clinical investigation. Bioactive TRAIL is a readily inactivated non-covalent homotrimer. We developed a covalent TRAIL trimer (TR3) which is more potent than recombinant TRAIL with improved stability. Furthermore, TR3 was found to be generically extensible in a stoichiometrically controlled manner. We demonstrate cell-specific targeting without loss of TRAIL activity. This proposal will explore the activity of a pancreas cancer-targeted TRAIL Trimer. Specific Aim 1: To determine the efficacy of multi-domain therapeutics comprised of a mesothelin targeting epitope (scFv) and a covalently linked TRAIL trimer (TR3) toward a panel of human pancreatic cancer cell lines in vitro and to elaborate mechanistic details regarding the role of tumor cell tethering in therapeutic activity. This aim focuses on the molecular biology of the scFv-TR3 fusion constructs. The goal is to determine to what extent an additional receptor/ligand interaction enhances the biologic activity of TR3, to determine whether these modifications potentiate TR3-induced apoptosis, and to delineate the mechanisms by which targeted TR3 has increased activity. Specific Aim 2: To determine the clinical feasibility of mesothelin-targeted TR3 therapy against primary human pancreatic tumor biopsies in vitro and in a xenogeneic mouse model of human pancreas cancer in vivo. This aim will establish whether primary cells from freshly resected pancreas tumors are responsive to TRAIL and furthermore will delineate the therapeutic activity of mesothelin- targeted TR3 to eradicate established human pancreatic tumors in a xenogeneic mouse tumor model. The results obtained from this second aim will establish both the patient population that a targeted TRAIL construct could help as well as be the first component of the preclinical safety and efficacy package for an IND using mesothelin-targeted TR3 for pancreas cancer therapy. PUBLIC HEALTH RELEVANCE: The 5-year survival rate of pancreas cancer patients (4%) remains dismal. New therapies are desperately needed and our TR3 platform technology provides an opportunity to combine a potent biologic agent (TRAIL) with targeting moieties to enhance its therapeutic potential. There is evidence in the literature that such a biologic approach to pancreas cancer therapy may be synergistic with standard of care therapies (such as gemcitabine or radiation). Our team of investigators has the experience necessary to bring promising biologic agents into clinical trials, increasing the likelihood and decreasing the time to translate successful animal studies into patients.

描述（申请人提供）：胰腺癌的踪迹——选择性细胞死亡（细胞凋亡） 简介：2008 年，胰腺癌是美国癌症相关死亡的第四大原因。该疾病的治疗进展甚微，年死亡率与年发病率几乎相同。迫切需要新的治疗策略。 TNF 相关凋亡诱导配体（TRAIL、Apo2L）对肿瘤表现出有效的、选择性的凋亡活性，目前正在临床研究中。生物活性 TRAIL 是一种易于失活的非共价同源三聚体。我们开发了一种共价 TRAIL 三聚体 (TR3)，它比重组 TRAIL 更有效，并且稳定性更高。此外，TR3被发现通常可以化学计量控制的方式扩展。我们证明了细胞特异性靶向而不损失 TRAIL 活性。该提案将探讨靶向胰腺癌的 TRAIL 三聚体的活性。具体目标 1：确定由间皮素靶向表位 (scFv) 和共价连接的 TRAIL 三聚体 (TR3) 组成的多域疗法在体外对一组人胰腺癌细胞系的功效，并详细阐述有关肿瘤细胞束缚在治疗活性中的作用的机制细节。 该目标侧重于 scFv-TR3 融合构建体的分子生物学。目的是确定额外的受体/配体相互作用在多大程度上增强了 TR3 的生物活性，确定这些修饰是否会增强 TR3 诱导的细胞凋亡，并描述靶向 TR3 增加活性的机制。具体目标 2：确定间皮素靶向 TR3 疗法针对体外原发性人胰腺肿瘤活检和体内人胰腺癌异种小鼠模型的临床可行性。 这一目标将确定来自新切除的胰腺肿瘤的原代细胞是否对 TRAIL 敏感，此外还将描述间皮素靶向 TR3 的治疗活性，以根除异种小鼠肿瘤模型中已建立的人类胰腺肿瘤。从第二个目标获得的结果将确定靶向 TRAIL 构建体可以帮助的患者群体，并成为使用间皮素靶向 TR3 治疗胰腺癌的 IND 临床前安全性和疗效包的第一个组成部分。 公共卫生相关性：胰腺癌患者的 5 年生存率 (4%) 仍然很低。迫切需要新的疗法，我们的 TR3 平台技术提供了将强效生物制剂 (TRAIL) 与靶向部分相结合的机会，以增强其治疗潜力。文献中有证据表明，这种胰腺癌的生物学治疗方法可能与标准护理疗法（例如吉西他滨或放射）具有协同作用。我们的研究团队拥有将有前景的生物制剂引入临床试验所需的经验，增加了将成功的动物研究转化为患者的可能性并缩短了时间。

项目成果

Potential targets for pancreatic cancer immunotherapeutics.

• DOI: 10.2217/imt.11.10
• 发表时间: 2011-04
• 期刊: Immunotherapy
• 影响因子: 2.8
• 作者: Dodson LF;Hawkins WG;Goedegebuure P
• 通讯作者: Goedegebuure P

Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.

膜近端 TRAIL 物种无法诱导短路凋亡信号传导：对药物开发和基本细胞因子生物学的影响。

• DOI: 10.1038/srep22661
• 发表时间: 2016
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Tatzel,Katharina;Kuroki,Lindsay;Dmitriev,Igor;Kashentseva,Elena;Curiel,DavidT;Goedegebuure,SPeter;Powell,MatthewA;Mutch,DavidG;Hawkins,WilliamG;Spitzer,Dirk
• 通讯作者: Spitzer,Dirk

A genetically encoded multifunctional TRAIL trimer facilitates cell-specific targeting and tumor cell killing.

• DOI: 10.1158/1535-7163.mct-10-0225
• 发表时间: 2010-07
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Spitzer D;McDunn JE;Plambeck-Suess S;Goedegebuure PS;Hotchkiss RS;Hawkins WG
• 通讯作者: Hawkins WG