Evaluation of non-invasive metabolic imaging biomarkers for novel RAF/MEK1/2-targeted anti-cancer agents

我们对导致癌症的精确过程的了解增加，揭示了RAF-MEK蛋白在这种疾病的发生和进展中的关键作用。事实上，目前正在开发许多旨在阻断RAF/MEK1/2（也称为RAF/MEK1/2抑制剂）的药物，最近FDA批准了抑制RAF家族蛋白BRAF成员的药物vemurafenib，用于治疗BRAF突变的皮肤癌（也称为黑色素瘤），为该策略的有效性提供了关键证据。基于给药阻断RAF/MEK的治疗方法目前正处于临床试验阶段。由于这些形式的治疗不会立即导致肿瘤大小的明显变化，因此需要传统的衡量临床反应的金标准，即治疗达到预期效果的早期指标（或生物标志物），以帮助评估患者的反应，并在必要时调整治疗计划。重要的是，特别是对患者来说，不需要手术干预的生物标志物，即非侵入性。成像技术，如磁共振（MR）提供了一个有用的工具，以非侵入性的方式跟踪肿瘤的生物学。该项目将使用非侵入性成像方法（主要是磁共振光谱（MRS）和成像（MRI））来跟踪已知在癌症中异常调节的肿瘤生物学的关键特征，即代谢，并了解癌细胞如何受到RAF/MEK1/2抑制的影响，以及当癌细胞对治疗无反应时，任何影响是如何变化的。研究将在植入小鼠体内的癌细胞和人类肿瘤以及参与抑制RAF/MEK1/2蛋白药物临床试验的患者样本中进行。我们的实验计划将包括各种细胞和分子测试，这些测试将与MRS和MRI测量相结合，以提供有关细胞和肿瘤代谢状态的信息，并了解这与RAF-MEK1/2抑制剂引起的细胞死亡等抗癌作用的关系。这项研究将帮助我们将实验室发现与RAF/MEK抑制剂药物对患者的实际作用联系起来。这些信息是至关重要的，将在未来帮助医生确定药物是否起到了预期的作用，最重要的是，当治疗不再有效时，可以立即寻求其他治疗方案。

Our increased knowledge of the precise processes that lead to cancer has revealed a key role for RAF-MEK proteins in the initiation and progression of this disease. In fact many drugs are now in development that aim to block RAF/MEK1/2 (also known as RAF/MEK1/2 inhibitors) and the recent FDA approval of the drug vemurafenib, which inhibits the BRAF member of the RAF family of proteins, for the treatment of skin cancers (also known as melanomas) with BRAF mutation provides key evidence for the effectiveness of this strategy.Treatments based on giving drugs to block RAF/MEK are now in clinical testing. As these forms of treatment are not expected to lead to immediately visible changes in tumour size, the traditional gold-standard for measuring clinical response, early indicators (or biomarkers) that the therapy is achieving its desired effects are required to help assess how the patient is responding and if necessary adjust the treatment plan. Of importance, in particular for the patient, are the biomarkers that do not require surgical intervention, i.e. non-invasive. Imaging techniques such as magnetic resonance (MR) provide a useful tool to follow the biology of tumours in a non-invasive way.This project will use non-invasive imaging approaches (mainly MR spectroscopy (MRS) and imaging (MRI)) to track a key feature of tumour biology that is known to be abnormally regulated in cancer, namely metabolism, and inform on how the cancer cells are affected by RAF/MEK1/2 inhibition and how any affects change when cancer cells become unresponsive to treatment. Studies will be performed in cancer cells and human tumours implanted in mice as well as samples from patients participating in a clinical trial of a drug that inhibits RAF/MEK1/2 proteins.Our experimental plan will include various cellular and molecular tests that will be combined with MRS and MRI measurements to provide information on the metabolic status of cells and tumours and understand how this relates to the anti cancer effects such as cell death caused by the RAF-MEK1/2 inhibitors.This research will help us relate our laboratory findings to what the RAF/MEK inhibitor drugs actually do in the patients. This information is crucial and will in the future help doctors determine whether a drug is acting as it is meant to and, crucially, when the therapy is no longer effective so other treatment options may be sought without delay.