Noninvasive Assessment of Cancer Responsiveness to Therapy by use of .....

使用......对癌症治疗反应进行无创评估

基本信息

批准号：
7490269
负责人：
DENNIS E HALLAHAN
金额：
$ 10.44万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-22 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7490269
关键词：
Abdomen Animals Apoptosis Avastin Binding Biodistribution Biological Biological Markers Biopsy Brain Cell Death Cell Survival Cells Chemistry Clinical Colon Carcinoma Complement Cytotoxic Chemotherapy Detection Development Disease Drug Kinetics EGF gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erbitux Evaluation Experimental Models Gastrointestinal Stromal Tumors Gefitinib Gleevec Goals Hypoxia Image Imaging Device Imaging technology Individual Invasive Laboratories Libraries Ligands Link Lung Magnetic Resonance Imaging Malignant Neoplasms Measures Methods Molecular Target Monitor Neoplasms Neoplasms in Vascular Tissue Nexavar Optics PDGFRB gene Patients Peptide Phage Display Library Peptides Phage Display Pharmacodynamics Physiological Positron-Emission Tomography Predisposition Production Protein Tyrosine Kinase Radiochemistry Radionuclide Imaging Receptor Protein-Tyrosine Kinases Renal Cell Carcinoma Research Research Personnel Resistance Resistance development Resources Roche brand of trastuzumab Sampling Errors Signal Pathway Signal Transduction Sutent System Technology Testing Time Treatment Protocols Tumor Volume Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors annexin A5 cancer care cancer imaging cancer therapy chemotherapy cytotoxic improved in vivo Cellular and Molecular Imaging Centers inhibitor/antagonist kinase inhibitor molecular imaging neoplastic novel optical imaging pathogen radiation effect receptor recombinant peptide response single photon emission computed tomography time interval tumor

项目摘要

Central Hypothesis: These aims will test the hypothesis that non-invasive imaging of cancer response can be achieved by use of recombinant peptides selected from phage-displayed libraries that bind within tumor blood vessels following treatment with tyrosine kinase inhibitors (TKIs). GOAL: The goal of this research is to assess cancer response to molecular targeted therapy by use recombinant peptides that bind to responding cancers. Specific kinase inhibitors, including receptor tyrosine kinase (RTKs) antagonists, are effective as single agents and enhance the cytotoxic effects of radiation and chemotherapy. RTK inhibitors interrupt signal transduction which is required for cell viability and thereby improve cancer susceptibility to cytotoxic therapy (Geng et al., 2001; Schueneman et al., 2003). RTK inhibitors have now been approved for many neoplastic diseases including renal cell carcinoma and gastrointestinal stromal tumors. Presently, cancer response is measured by the assessment of tumor volumes or by repeated biopsy to analyze pharmacodynamics. These methods of monitoring cancer response are inefficient because volume changes typically require therapy for prolonged time intervals. Neoplasms within the brain, lung or abdomen are not amenable to sequential biopsies. Furthermore, biopsies can result in sampling error so that the response to therapy is not accurately assessed. One other consideration is the re-evaluation of the development of resistance in cancer as resistant cells repopulate a neoplasm. Although peptide ligands such as Annexin V have been used to assess apoptosis, noninvasive imaging to assess cancer responsiveness to therapy has not developed a useful imaging tool for assessment of cell death. We have therefore utilized phage displayed peptide libraries (over a billion peptide ligands) to select peptides that bind to responding tumors but not to nonresponding tumors. One peptide, HVGGSSV, is effective at assessing cancer response to RTK inhibitors. This peptide maintains selective binding to responding cancers when linked to gamma emitters. We will study the HVGGSSV peptide which rapidly assesses tumor vascular response to VEGF RTK inhibitors. This new paradigm in cancer management promises to improve our ability to tailor therapy specifically to an individual patient in a manner that is more analogous to the management of bacterial pathogens in that susceptibility to therapy can be predetermined. This is platform technology that will prove the principle that peptide biomarkers are effective at rapidly assessing cancer susceptibility to molecular targeted therapy.

中心假设：这些目标将检验以下假设：癌症反应的非侵入性成像可以可以通过使用从结合肿瘤内结合的噬菌体斑点库中选择的重组肽来实现用酪氨酸激酶抑制剂（TKI）治疗后的血管。目标：这项研究的目的是通过使用评估癌症对分子靶向治疗的反应与反应癌症结合的重组肽。特定的激酶抑制剂，包括受体酪氨酸激酶（RTK）拮抗剂，有效为单个药物并增强放射线和化学疗法的细胞毒性作用。 RTK抑制剂中断信号细胞活力所需的转导，从而提高癌症对细胞毒性疗法的敏感性（Geng等，2001； Schueneman等，2003）。 RTK抑制剂现已被批准用于许多肿瘤包括肾细胞癌和胃肠道肿瘤在内的疾病。目前，癌症反应是通过评估肿瘤体积或反复的活检来分析药效学。这些监测癌症反应的方法效率低下，因为体积变化通常需要治疗延长时间间隔。大脑，肺或腹部内的肿瘤不适合顺序活检。此外，活检可能会导致抽样误差，因此对治疗的反应不准确评估。另一个考虑因素是重新评估癌症中抗药性的发展为抗药性细胞再填充肿瘤。尽管已使用肽配体（例如膜联蛋白V）来评估凋亡，无创成像以评估癌症对治疗的反应性尚未产生有用的用于评估细胞死亡的成像工具。因此，我们利用噬菌体显示了肽库（在十亿肽配体）选择与反应肿瘤结合但不与无反应肿瘤结合的肽。一种肽HVGGSSV可有效评估癌症对RTK抑制剂的反应。该肽保持选择性结合到响应癌症与伽马发射器相关时。我们将研究HVGGSSV肽迅速评估对VEGF RTK抑制剂的肿瘤血管反应。这个新的癌症范式管理层有望以某种方式提高我们针对单个患者专门定制治疗的能力这与细菌病原体的治疗更类似，因为可以预先确定对治疗的敏感性。这是平台技术，它将证明肽生物标志物有效的原则快速评估癌症对分子靶向治疗的敏感性。