Mechanisms of uptake of 18F-FDG in an in vivo model of c-kit induced neoplasia

肿瘤生物学领域的最新进展已经在分子靶向抗肿瘤药物的开发中产生了强烈的兴趣。这些靶向药物有望产生比常规细胞毒性治疗更高的治疗指数和更少的副作用。然而，由于受给定治疗影响的细胞过程的复杂性质，以及将新药引入临床的高成本，在药物开发过程的早期确定靶向治疗的作用机制和体内功能效应是重要的。胃肠道间质瘤（GIST）是合理设计的药物已成功使用的癌症的一个主要例子。GIST通常与c-kit（编码细胞表面蛋白的基因）的激活突变有关。一种新的药物，伊马替尼，抑制突变的c-kit的活性，并阻止许多GIST的生长。然而，随着时间的推移，许多GIST对伊马替尼产生耐药性，需要开发其他治疗方法。不幸的是，由于缺乏测试新药的良好模型系统和确定治疗反应的强大诊断程序，这一点受到了阻碍。我们现在已经开发了一种GIST小鼠模型，其生长和对治疗的反应与人类GIST相似。此外，使用专门为小动物研究设计的成像技术，我们可以快速监测和评估治疗期间的反应变化。我们建议使用模型系统与小动物成像技术来定义GIST响应或对伊马替尼产生耐药性的机制。这涉及定义细胞内的特定分子，这些分子在伊马替尼治疗后改变活性，以及测试一系列可能与耐药性有关的基因突变。该研究的结果将有助于确定GIST治疗的新靶点，并验证可能广泛应用于监测靶向抗癌治疗的成像策略。

Recent advances in the field of tumour biology have created strong interest in development of molecularly targeted anti-tumour drugs. These targeted drugs are expected to yield higher therapeutic indices with fewer side effects than conventional cytotoxic treatments. However, due to the complicated nature of cellular processes affected by a given treatment, and the high cost of bringing new drugs to the clinic, it is important to define both mechanisms of action and in vivo functional effects of targeted therapies early in the drug development process. Gastrointestinal stromal tumour (GIST) is a prime example of a cancer for which a rationally designed drug has been successfully used. GISTs are often associated with activating mutations in c-kit, a gene encoding a cell surface protein. A new drug, Imatinib, inhibits the activity of mutated c-kit and blocks growth of many GISTs. However, over time many GISTs become resistant to Imatinib creating the need to develop additional treatments. Unfortunately, this has been hampered by lack of both a good model system for testing new drugs and robust diagnostic procedures for defining response to treatment. We have now developed a mouse model of GIST that grows and responds to treatment in a similar manner to human GIST. Furthermore, using imaging technology specifically designed for small animal studies, we can quickly monitor and evaluate changes in response during treatment. We propose to use the model system together with small animal imaging technology to define mechanisms by which GISTs respond or become resistant to Imatinib. This involves defining specific molecules within cells that change activity after Imatinib treatment as well as testing a series of gene mutations that may be involved in drug resistance. The results of the study will help to define new targets for GIST treatment as well as validate the imaging strategy that may have wide application to monitoring targeted anti-cancer therapies.