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（由申请人提供）：成纤维细胞活化蛋白（FAP）是一种膜锚定的蛋白，其在上皮癌中肿瘤基质成纤维细胞的选择性表达独特，但不是由上皮癌细胞，正常的正常成纤维细胞或其他正常组织。 FAP表达对肿瘤基质的特异性以及FAP酶活性抑制剂的最新临床发展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。该研究计划的远距离目标是通过破坏其对肿瘤生长，侵袭和转移的支持性影响来靶向肿瘤基质成纤维细胞。该提案的目的是确定Val-Boropro对FAP酶活性的扰动而产生的生物学作用，Val-Boropro是FAL的第一个也是唯一的FAP抑制剂在临床试验中接受评估的FAP抑制剂。要测试的中心假设是，使用Val-Boropro抑制FAP会减轻人类胰腺癌的生长。该假设是根据我们的观察结果提出的，即1）绝大多数胰腺癌诱导FAP的基质成纤维细胞表达，2）动物模型中的FAP过表达增强了肿瘤的生长，而3）肿瘤的生长被FAP酶促活性的废除减弱。拟议的研究的理由是，在最近的临床试验中，射线照相反应证明了Val-Boropro似乎具有抗肿瘤活性。因此，我们旨在确定FAP酶促抑制的临床影响，对接受Val-Boropro治疗的局部晚期胰腺癌患者。一项II期研究将检验中心假设，即施用FAP抑制剂Val-boropro将在胰腺癌患者中表现出抗肿瘤活性，从而利用Val-Boropro和Gemcitabine治疗局部晚期胰腺癌患者的协同作用。该临床试验的主要终点是无进展生存。此外，我们旨在通过对val-boropro治疗对胰腺癌标本的影响进行单独的临床试验来确定肿瘤部位的FAP酶活性的变化，该试验在计划进行胰腺十二二二核切除术的患者的窗户研究中。局部胰腺癌的患者将在手术切除前接受5天的VAL-BOROPRO，从而可以直接对治疗的肿瘤采样，以确定FAP酶活性抑制程度，以及FAP对肿瘤部位的任何下游影响。如果在肿瘤部位的胰腺癌患者中可以看到胰腺癌患者的临床益处，那么与公共荒地的相关性是，这将被认为足够显着，可以建立基质抑制的临床范围，作为一种新型的临床策略来治疗胰腺癌。公共卫生声明如果在胰腺癌患者中看到临床益处，并在肿瘤部位相关的FAP酶促抑制作用，那么与公共卫生的相关性是，这将被认为是足够重要的，可以建立基质抑制作用的临床范围，作为治疗胰腺癌的新型临床策略。