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

中心假设：这些目标将检验癌症反应的非侵入性成像可以 通过使用选自噬菌体展示文库的重组肽来实现 酪氨酸激酶抑制剂（TKI）治疗后的血管。 目的：本研究的目的是评估癌症对分子靶向治疗的反应， 重组肽结合到相应的癌症。 特异性激酶抑制剂，包括受体酪氨酸激酶（RTK）拮抗剂，作为单一的治疗有效。 药物和增强放射和化学疗法的细胞毒性作用。RTK抑制器中断信号 细胞存活所需的转导，从而提高癌症对细胞毒性疗法的敏感性 (Geng等，2001; Schueneman等人，2003年）。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间质瘤的疾病。目前，癌症反应是 通过评估肿瘤体积或通过重复活检来测量以分析药效学。这些 监测癌症反应的方法是低效的，因为体积变化通常需要治疗， 延长时间间隔。脑、肺或腹部内的新生儿不适合连续治疗。 活组织检查此外，活组织检查可能导致采样误差，使得对治疗的反应不准确。 评估。另一个考虑是重新评估癌症耐药性的发展， 细胞重新填充肿瘤。尽管肽配体如膜联蛋白V已被用于评估 细胞凋亡，非侵入性成像评估癌症对治疗的反应性还没有开发出一种有用的 用于评估细胞死亡的成像工具。因此，我们利用噬菌体展示肽文库（超过1000个）。 10亿肽配体）以选择与应答肿瘤结合但不与无应答肿瘤结合的肽。 一种肽HVGGSSV可有效评估癌症对RTK抑制剂的反应。这种肽维持 当与γ发射体连接时，选择性地结合到响应的癌症。我们将研究HVGGSSV多肽 其快速评估肿瘤血管对VEGF RTK抑制剂的反应。这种癌症的新模式 管理层承诺提高我们的能力，以某种方式为个别患者量身定制治疗， 这更类似于细菌病原体的管理，因为对治疗的敏感性可以预先确定。 这是一种平台技术，它将证明肽生物标志物有效的原理， 快速评估癌症对分子靶向治疗的敏感性。

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.