Pharmacodynamic Assessment of RTK Inhibitors in Cancer

RTK 抑制剂在癌症中的药效学评估

• 批准号: 6864344
• 负责人: DENNIS E HALLAHAN
• 金额: $ 26.94万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-23 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864344
• 关键词: angiogenesis inhibitors; antineoplastics; athymic mouse; bioimaging /biomedical imaging; cell line; drug screening /evaluation; human genetic material tag; imaging /visualization /scanning; kinase inhibitor; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplastic growth; nonhuman therapy evaluation; phage display; pharmacokinetics; radiosensitizer; vascular endothelial growth factors

DESCRIPTION (provided by applicant): The limitation of present assessment of response to therapy is that patients are treated for 2 months before tumor volumes are measured to reassess effectiveness of the drug. The goal of this research is to develop systems for the rapid assessment of cancer responsiveness and susceptibility to tyrosine kinase inhibitors (TKIs) by use of recombinant peptides that bind to responding cells. These aims will test the central hypothesis that non-invasive imaging of cancer response can be achieved by use of recombinant peptides selected from a phage-displayed libraries that bind within tumor blood vessels following treatment with TKIs and cytotoxic therapy. PET, SPECT and gamma camera imaging will be used to rapidly monitor the response of cancer to TKIs. One model includes VEGF receptor TKIs that enhance the cytotoxic effects of radiation in the tumor microvasculature. This results in apoptosis of the tumor endothelium and subsequent activation of inflammation and thrombotic cascades. Our preliminary data indicates that VEGF receptor TKIs enhance the effects of radiation within tumor microvasculature resulting in improved tumor control. Cancer susceptibility to TKIs has been evaluated primarily by tumor tissue sectioning and staining. This pharmacodynamic approach is not entirely feasible in patients with brain tumors and lung cancer primaries. For that reason, we have developed the hypotheses that recombinant peptides from phage-displayed peptide libraries can be selected that bind to apoptotic endothelium and to receptors activated in response to therapy. These peptides in turn can be labeled with internal emitters to provide a means of non-invasive monitoring of responsiveness to therapy. The physiologic response to therapy is seen within 24 hours of therapy, which provides a rapid assessment using non-invasive means. We utilized phage displayed peptide libraries to select peptides that bind within treated tumor blood vessels. We will study these peptides with the intention of monitoring tumor blood vessel response during therapy with RTK inhibitors and radiation. We hypothesize that recombinant peptides will bind to cells undergoing apoptosis and provide a means to non-invasively assess cancer response to TKI therapy. The studies of the RGD peptide pneumatic imaging of tumor vasculature response has shown that this simple amino acid sequence binds to activated receptor that is non-specific and achieves binding to other tissues in addition to tumor [Hallahan, 2001]. For that reason, we have developed recombinant peptide that binds more specifically to irradiated tumor blood vessels. In the present investigation, we will test the hypothesis that these recombinant peptides bind selectively to microvasculature of treated tumors.

描述（由申请人提供）：当前对治疗反应的评估的局限性是，在测量肿瘤体积以重新评估药物的有效性之前，患者进行了2个月的治疗。这项研究的目的是通过使用与响应细胞结合的重组肽来快速评估癌症反应性和对酪氨酸激酶抑制剂（TKI）的敏感性的系统。这些目的将检验以下中心假设：通过使用从噬菌体斑点播种的文库中选择的重组肽可以实现癌症反应的非侵入性成像，这些肽在用TKIS治疗和细胞毒性疗法治疗后结合了肿瘤血管内的结合。 PET，SPECT和伽马相机成像将用于快速监测癌症对TKI的反应。一个模型包括VEGF受体TKI，可增强肿瘤微脉管系统中辐射的细胞毒性作用。这导致肿瘤内皮细胞凋亡以及随后的炎症和血栓级联反应。我们的初步数据表明，VEGF受体TKI增强了肿瘤微脉管系统内辐射的影响，从而改善了肿瘤控制。癌症对TKI的敏感性主要通过肿瘤组织切片和染色来评估。这种药效方法在脑肿瘤和肺癌初选的患者中并不完全可行。因此，我们开发了可以选择与凋亡肽库中的重组肽的假设，可以选择与凋亡的内皮结合，并响应于治疗而激活的受体。这些肽反过来又可以用内部发射器标记，以提供对治疗反应性的无创手段。在治疗后的24小时内可以看到对治疗的生理反应，该治疗使用非侵入性手段进行了快速评估。我们利用噬菌体显示肽库来选择在处理过的肿瘤血管内结合的肽。我们将研究这些肽，以监测RTK抑制剂和辐射治疗期间肿瘤血管反应。我们假设重组肽将与经历凋亡的细胞结合，并提供一种非侵入性评估癌症对TKI治疗反应的方法。对肿瘤脉管系统反应的RGD肽气动成像的研究表明，这种简单的氨基酸序列与非特异性的活化受体结合，除了肿瘤外，还与其他组织结合了其他组织[Hallahan，2001]。因此，我们开发了重组肽，该肽更具体地与辐照的肿瘤血管结合。在本研究中，我们将检验以下假设：这些重组肽与处理过的肿瘤的微脉管系统有选择性结合。