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

简介：胰腺癌选择性细胞死亡(细胞凋亡)简介：胰腺癌是2008年美国癌症相关死亡的第四大原因。该病的管理进展甚微，年死亡率与年发病率几乎相同。迫切需要新的治疗策略。肿瘤坏死因子相关的凋亡诱导配体(TRAIL，Apo2L)具有较强的选择性抗肿瘤细胞凋亡活性，目前正处于临床研究阶段。生物活性TRAIL是一种易灭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以化学计量学控制的方式一般可扩展。我们展示了在不损失TRAIL活性的情况下的细胞特异性靶向。这项提案将探索一种针对胰腺癌的试验三聚体的活性。具体目标1：确定由间硫蛋白靶向表位(ScFv)和共价连接的TRAIL三聚体(TR3)组成的多区域疗法在体外对一组人胰腺癌细胞株的疗效，并阐述肿瘤细胞系系在治疗活性中所起作用的机制细节。这一目标集中在scFv-TR3融合构建物的分子生物学上。我们的目标是确定额外的受体/配体相互作用在多大程度上增强TR3的生物学活性，确定这些修饰是否增强TR3诱导的细胞凋亡，并描绘靶向TR3增强活性的机制。特定目的2：在体外和体内的人胰腺癌异种小鼠模型中，确定以间充质素靶向TR3治疗原发人胰腺癌活检组织的临床可行性。这一目标将确定新切除的胰腺肿瘤的原代细胞是否对TRAIL有反应，并进一步描述以间硫蛋白为靶点的TR3在异种小鼠肿瘤模型中根除已建立的人胰腺肿瘤的治疗活性。从第二个目标获得的结果将既确定靶向试验构建可能有助于的患者群体，也将成为使用METHELIN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。 公共卫生相关性：胰腺癌患者的5年存活率(4%)仍然令人沮丧。我们迫切需要新的治疗方法，我们的TR3平台技术提供了一个机会，将有效的生物制剂(TRAIL)与靶向部分结合起来，以增强其治疗潜力。文献中有证据表明，胰腺癌治疗的生物学方法可能与标准的治疗方法(如吉西他滨或放射治疗)协同作用。我们的研究团队拥有将有前途的生物制剂带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减少了时间。

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.