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

简介：2008年，胰腺癌是美国癌症相关死亡的第四大原因。在对这种疾病的管理方面几乎没有取得进展，年死亡率与年发病率几乎相同。迫切需要新的治疗策略。tnf相关的凋亡诱导配体（TRAIL, Apo2L）显示出对肿瘤有效的选择性凋亡活性，目前正在临床研究中。生物活性TRAIL是一种容易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，稳定性更好。此外，发现TR3在化学计量控制的方式下具有一般可扩展性。我们证明了在不丧失TRAIL活性的情况下细胞特异性靶向。该提案将探索胰腺癌靶向TRAIL三聚体的活性。特异性目的1：确定由间皮素靶向表位（scFv）和共价连接TRAIL三聚体（TR3）组成的多结构域治疗药物在体外对一组人胰腺癌细胞系的疗效，并详细阐述肿瘤细胞栓系在治疗活性中的作用的机制细节。本研究的重点是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，确定这些修饰是否增强了TR3诱导的细胞凋亡，并描述靶向TR3增加活性的机制。特异性目的2：确定间皮素靶向TR3治疗原发性人胰腺肿瘤活检的体外和体内异种人胰腺癌小鼠模型的临床可行性。目的是确定新切除胰腺肿瘤的原代细胞是否对TRAIL有反应，并进一步描述间皮素靶向TR3在异种小鼠肿瘤模型中根除已建立的人类胰腺肿瘤的治疗活性。从第二个目标中获得的结果将确定靶向TRAIL构建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临床前安全性和有效性包的第一个组成部分。

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.