Clinical Inhibition of the Stromal Target Fibroblast Activation Protein

基质靶成纤维细胞激活蛋白的临床抑制

• 批准号: 7256694
• 负责人: JONATHAN D CHENG
• 金额: $ 13.68万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-19 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256694
• 关键词: Animal Model; Antiplasmin; Archives; Attenuated; Carcinoma; Clinical; Clinical Trials; Development; Dipeptidyl Peptidases; End Point; Evaluation; Excision; Fibroblasts; Goals; Growth; Human; Immunohistochemistry; Lead; Localized; Malignant Epithelial Cell; Malignant neoplasm of pancreas; Membrane; Membrane Glycoproteins; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Pancreaticoduodenectomy; Pathway interactions; Patient Schedules; Patients; Phase II Clinical Trials; Plasma; Progression-Free Survivals; Protein Inhibition; Protein Overexpression; Proteins; Public Health; Range; Research; Sampling; Site; Specificity; Specimen; Stromal Change; Stromal Neoplasm; Testing; Therapeutic Agents; Work; base; cancer therapy; day; expectation; fibroblast-activating factor; gemcitabine; in vivo; inhibitor/antagonist; innovation; novel; programs; protein expression; response; selective expression; therapeutic target; therapy development; tumor; tumor growth

DESCRIPTION (provided by applicant): Fibroblast activation protein (FAP) is a membrane-anchored protein that is unique in its selective expression by tumor stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. The specificity of FAP expression for the tumor stroma, as well as the recent clinical development of inhibitors of FAP enzymatic activity, provides a unique opportunity to investigate and manipulate stromal contributions to tumor growth and invasion. The long-range goal of this research program is to therapeutically target tumor stromal fibroblasts by disrupting their supportive influences on tumor growth, invasion, and metastasis. The objective of this proposal is to determine the biologic effects resulting from perturbations of FAP enzymatic activity by Val-boroPro, the first and only inhibitor of FAP undergoing evaluation in clinical trials. The central hypothesis to be tested is that inhibition of FAP using Val-boroPro will attenuate the growth of pancreas cancer in humans. This hypothesis is formulated based on our observations that 1) the vast majority of pancreas cancers induce stromal fibroblast expression of FAP, 2) FAP overexpression in an animal model potentiates tumor growth, and 3) tumor growth is attenuated by abrogation of FAP enzymatic activity. The rationale for the proposed research is that Val-boroPro appears to have anti-tumor activity as demonstrated by radiographic responses in recent clinical trials. We thus aim to determine the clinical impact of FAP enzymatic inhibition in patients with locally advanced pancreas cancers treated with Val-boroPro. A phase II study will test the central hypothesis that administration of the FAP inhibitor Val-boroPro will demonstrate anti-tumor activity in patients with pancreas cancer, exploiting the synergistic effects of Val-boroPro and gemcitabine to treat patients with locally advanced pancreas cancer. The primary endpoint of this clinical trial will be progression-free survival. In addition we aim to determine changes in FAP enzymatic activity at tumor site with Val-boroPro treatment by conducting a separate clinical trial studying the effects of Val-boroPro treatment on pancreas cancer specimens in a window study of patients scheduled to undergo pancreaticoduodenectomy. Patients with localized pancreas cancer will receive 5 days of Val-boroPro prior to surgical resection, thus enabling direct sampling of treated tumors to determine the degree of inhibition of FAP enzymatic activity, and any downstream effects of FAP at the tumor site. If clinical benefit is seen in patients with pancreas cancer with associated FAP enzymatic inhibition at the tumor site, the relevance to public heath is that this will be considered sufficiently significant to establish the clinical paradigm of stromal inhibition as a novel clinical strategy to treat pancreatic cancer. PUBLIC HEALTH STATEMENT If clinical benefit is seen in patients with pancreas cancer with associated FAP enzymatic inhibition at the tumor site, the relevance to public heath is that this will be considered sufficiently significant to establish the clinical paradigm of stromal inhibition as a novel clinical strategy to treat pancreatic cancer.

描述（申请人提供）：成纤维细胞激活蛋白（FAP）是一种膜锚定蛋白，其独特之处在于其在上皮癌中的肿瘤基质成纤维细胞中选择性表达，但在上皮癌细胞、正常成纤维细胞或其他正常组织中不表达。肿瘤基质中 FAP 表达的特异性以及 FAP 酶活性抑制剂的最新临床开发，为研究和操纵基质对肿瘤生长和侵袭的贡献提供了独特的机会。该研究计划的长期目标是通过破坏肿瘤基质成纤维细胞对肿瘤生长、侵袭和转移的支持性影响来治疗靶向肿瘤基质成纤维细胞。该提案的目的是确定 Val-boroPro 对 FAP 酶活性的干扰所产生的生物效应，Val-boroPro 是第一个也是唯一一个正在临床试验中进行评估的 FAP 抑制剂。待测试的中心假设是，使用 Val-boroPro 抑制 FAP 将减弱人类胰腺癌的生长。这一假设是基于我们的观察得出的：1) 绝大多数胰腺癌诱导基质成纤维细胞表达 FAP，2) 动物模型中 FAP 过度表达会增强肿瘤生长，3) 消除 FAP 酶活性会减弱肿瘤生长。拟议研究的基本原理是，Val-boroPro 似乎具有抗肿瘤活性，最近临床试验中的放射照相反应证明了这一点。因此，我们的目的是确定 FAP 酶抑制对接受 Val-boroPro 治疗的局部晚期胰腺癌患者的临床影响。 II 期研究将测试以下中心假设：使用 FAP 抑制剂 Val-boroPro 将在胰腺癌患者中表现出抗肿瘤活性，利用 Val-boroPro 和吉西他滨的协同作用来治疗局部晚期胰腺癌患者。该临床试验的主要终点是无进展生存期。此外，我们的目标是通过在计划接受胰十二指肠切除术的患者的窗口研究中进行一项单独的临床试验，研究 Val-boroPro 治疗对胰腺癌标本的影响，以确定 Val-boroPro 治疗后肿瘤部位 FAP 酶活性的变化。局部胰腺癌患者将在手术切除前接受 5 天的 Val-boroPro，从而能够直接对治疗的肿瘤进行取样，以确定 FAP 酶活性的抑制程度以及 FAP 在肿瘤部位的任何下游影响。如果在肿瘤部位进行相关 FAP 酶抑制的胰腺癌患者中看到临床益处，那么与公众健康的相关性在于，这将被认为足够重要，足以建立基质抑制的临床范例作为治疗胰腺癌的新型临床策略。公共卫生声明如果在肿瘤部位进行相关 FAP 酶抑制的胰腺癌患者中看到临床益处，那么与公共卫生的相关性是，这将被认为足够重要，足以建立基质抑制的临床范例作为一种新的临床策略治疗胰腺癌。