PET imaging of the tumor microenvironment for cancer detection

用于癌症检测的肿瘤微环境 PET 成像

• 批准号: 9585261
• 负责人: Thaddeus J. Wadas
• 金额: $ 20.23万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9585261
• 关键词: Affinity; Amino Acids; Animals; Autoradiography; Benign; Biodistribution; Biological Assay; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Detection; Carbon; Cells; Clinic; Clinical; Clinical Treatment; Clinical Trials; Complex; Data; Detection; Development; Diagnosis; Drug Kinetics; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Functional Imaging; Goals; Heterogeneity; High Pressure Liquid Chromatography; Human; Image; Immune; Immune response; Immunoglobulin G; In Vitro; Label; Literature; Liver Microsomes; Lymphatic; Malignant neoplasm of pancreas; Mesenchymal Stem Cells; Microscopy; Molecular Probes; Monitor; Monoclonal Antibody F19; Mus; Nature; Neoplasm Metastasis; Nude Mice; Outcome; Pancreas; Pancreatic carcinoma; Patient Monitoring; Patients; Phenotype; Population; Positron-Emission Tomography; Radioactivity; Radiochemistry; Radiolabeled; Radiopharmaceuticals; Recurrence; Resolution; Scientist; Serine Protease; Specificity; Specimen; Stromal Cells; Survival Rate; T cell response; Testing; Therapeutic; Tissues; Tumor Tissue; Tumor-Derived; Vascular Endothelial Cell; Work; X-Ray Computed Tomography; Xenograft procedure; base; cancer cell; cancer imaging; carcinogenesis; diagnostic accuracy; fibroblast activation protein alpha; fluorodeoxyglucose; imaging agent; imaging biomarker; imaging capabilities; improved; in vivo; inhibitor/antagonist; interest; lipophilicity; lymph nodes; molecular imaging; mortality; mouse model; novel; novel therapeutic intervention; overexpression; pancreas imaging; pancreatic neoplasm; precision medicine; quantitative imaging; radiotracer; response; scaffold; small molecule; stellate cell; success; targeted cancer therapy; therapeutic development; therapy resistant; tumor; tumor microenvironment

PROJECT SUMMARY Pancreatic cancer (PDAC), characterized by its aggressive nature and extensive fibrosis within the tumor microenvironment (TME), has a dismal 5-year survival rate of only 7%. Pancreatic tumors consist of abundant extracellular matrix and tumor-associated fibroblasts (TAFs) that express fibroblast activation protein alpha (FAP). FAP+TAFs promote tumor development and progression in the pancreas through remodeling the extracellular matrix and suppressing local CD8+ T cell response during carcinogenesis. Pancreatic tumors contain FAP+TAFs; the degree of FAP expression positively correlates with lymph node status, larger tumor size, faster recurrence, and worse clinical outcome. Since FAP is overexpressed in tumor tissue and has basal expression in benign tissue, it has value as a target for cancer therapies that modulate tumor-stroma interactions. However, quantifying FAP expression in vivo with available molecular probes is difficult, and a key unanswered question is whether PET-based molecular imaging agents can detect FAP+TAFs in the PDAC tumor stroma. In this application we hypothesize that targeting fibroblast activation protein alpha (FAP) – a unique biomarker found on tumor-associated fibroblasts (TAFs) in the PDAC TME, will allow us to detect and quantify the TME in vivo using PET. To test this hypothesis, we propose two specific aims. In the first aim we will synthesize novel FAP inhibitors that are based upon a cyanopyrrolidine scaffold. These molecules will be assessed for FAP selectivity using plate-based IC50 and affinity assays, lipophilicity (log P) and in vitro stability using human liver microsomes. In Aim 2 the most promising compounds will be radiolabeled with carbon-11 and evaluated in biodistribution and small animal PET/CT studies using a PDX orthotopic xenograft mouse model, which recapitulates the heterogeneity of PDAC tumors observed in the clinic. Radioactivity accumulation will be quantified from regions of interest (ROIs) drawn around the tumor on the co-registered PET/CT images. Finally, multi-spectral microscopy will be conducted on murine tissue specimens to assess radiotracer specificity and correlate the radioactivity accumulation with FAP and other biomarkers that describe a TAF phenotype. If successful, this work will immediately impact how basic scientists study FAP expression and the pancreatic TME. This work could inform new paradigms for pancreatic cancer imaging that can be exploited as part of an integrated strategy for much-needed improvements in diagnosis and management of pancreatic carcinoma.

项目摘要 胰腺癌（PDAC），以其侵袭性和肿瘤内广泛纤维化为特征 微环境（TME），5年生存率只有7%。胰腺肿瘤由丰富的 细胞外基质和表达成纤维细胞活化蛋白α的肿瘤相关成纤维细胞（TAF） （FAP）。FAP+TAFs通过重塑胰腺组织促进胰腺肿瘤的发生和发展。 细胞外基质和抑制局部CD 8 + T细胞反应在癌变过程中。胰腺肿瘤 含有FAP+TAFs; FAP表达的程度与淋巴结状态、较大的肿瘤 更快的复发和更差的临床结果。由于FAP在肿瘤组织中过表达， 在良性组织中的表达，它具有作为调节肿瘤间质的癌症治疗的靶点的价值。 交互.然而，用可用的分子探针在体内定量FAP表达是困难的，并且是关键。 尚未回答的问题是基于PET的分子成像剂是否可以检测PDAC中的FAP+ TAF 肿瘤间质在本申请中，我们假设靶向成纤维细胞活化蛋白α（FAP）- a PDAC TME中肿瘤相关成纤维细胞（TAF）上发现的独特生物标志物将使我们能够检测并 使用PET量化体内TME。为了验证这一假设，我们提出了两个具体目标。在第一个目标中， 将合成基于氰基吡咯烷骨架的新型FAP抑制剂。这些分子将 使用基于板的IC 50和亲和测定评估FAP选择性、亲脂性（log P）和体外稳定性 使用人类肝微粒体。在目标2中，最有前途的化合物将用碳-11进行放射性标记 并使用PDX原位异种移植小鼠在生物分布和小动物PET/CT研究中进行评价 模型，其概括了在临床中观察到的PDAC肿瘤的异质性。放射性 将从共同配准的肿瘤周围绘制的感兴趣区域（ROI）量化累积。 PET/CT图像。最后，将对小鼠组织标本进行多光谱显微镜检查，以评估 放射性示踪剂特异性，并将放射性累积与FAP和其他描述 a TAF表型。如果成功，这项工作将立即影响基础科学家如何研究FAP表达 和胰腺TME。这项工作可以为胰腺癌成像提供新的范例， 作为一项综合战略的一部分，用于急需改善的诊断和管理， 胰腺癌