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

描述（由申请人提供）：关于胰腺癌的TRAIL-选择性细胞死亡（凋亡）简介：胰腺癌是2008年美国癌症相关死亡率的第四大原因。在防治这一疾病方面进展甚微，年死亡率与年发病率几乎相同。迫切需要新的治疗策略。肿瘤坏死因子相关凋亡诱导配体（TRAIL，Apo 2L）对肿瘤显示出有效的、选择性的凋亡活性，目前正在进行临床研究。生物活性TRAIL是一种容易失活的非共价同源三聚体。我们开发了共价TRAIL三聚体（TR 3），其比重组TRAIL更有效，具有改善的稳定性。此外，TR 3被发现是一般可扩展的化学计量控制的方式。我们证明了细胞特异性靶向而不损失TRAIL活性。该提案将探索胰腺癌靶向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（TR 3）组成的多结构域治疗剂对一组人胰腺癌细胞系的体外疗效，并详细说明肿瘤细胞系链在治疗活性中的作用的机制细节。 该目的集中于scFv-TR 3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TR 3的生物活性，以确定这些修饰是否增强TR 3诱导的细胞凋亡，并描绘靶向TR 3具有增加活性的机制。具体目标二：确定间皮素靶向TR 3疗法在体外针对原发性人胰腺肿瘤活组织检查和在人胰腺癌的异种小鼠模型体内针对原发性人胰腺肿瘤活组织检查的临床可行性。 该目的将确定来自新鲜切除的胰腺肿瘤的原代细胞是否响应于TRAIL，并且还将描述间皮素靶向的TR 3根除异种小鼠肿瘤模型中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建立靶向TRAIL构建体可以帮助的患者群体以及使用间皮素靶向TR 3用于胰腺癌治疗的IND的临床前安全性和有效性包的第一组分。 公共卫生相关性：胰腺癌患者的5年生存率（4%）仍然令人沮丧。迫切需要新的疗法，我们的TR 3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，这种胰腺癌治疗的生物学方法可能与标准治疗（如吉西他滨或放射）具有协同作用。我们的研究人员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缩短了时间。

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.