Targeting mechanisms of radiation resistance

这种方法的一个例子是我的实验室使用MEK抑制剂AZD6244。我的实验室在体外和体内证明了MEK抑制作为辐射增敏剂的治疗潜力，(12)评估了同时化疗对MEK抑制的放射增敏效果的影响，(13)确定了可以预测这种方法有效性的生物标记物，并强调了当这一途径成为靶向时的辐射增敏机制。(12-14)这项工作最终在NCI启动了CTEP赞助的I期试验，调查MEK抑制与目前标准的放化疗相结合在局部晚期直肠癌患者的新辅助治疗中的作用。目前有三个开放的和两个完成的I期临床试验，评估MEK抑制结合放射和化疗治疗局部癌症。我们最近发现了更多的化合物，它们在体外显示出作为辐射增敏剂的初步效果。我们过去用来选择研究试剂的方法在确定辐射敏感剂方面是有效的。然而，随着我们根据我的方案13-C-0119收集前列腺癌患者的肿瘤组织和临床结果数据，这种方法正在发展。这项临床试验将使我们能够评估接受放射治疗的局限性前列腺癌患者局部失败的多种生物学、临床和放射学预测因素。在这项研究中登记的患者接受了前处理、多参数MRI和MRI引导下的前列腺内所有肿瘤的研究活组织检查。放射治疗后，符合生化失败标准的PSA升高的患者接受重复的前列腺多参数MRI检查，并在MRI引导下对永久性肿瘤进行研究活检。分析肿瘤的分子特征，以评估失败的预测因素，并研究肿瘤在放射治疗后的演变。来自上述组织研究的数据将被挖掘出来，以产生前列腺癌辐射抵抗的候选途径列表。这些数据将为实验室研究提供信息，这些研究旨在确定这些途径在辐射反应中的重要性。

An example of this approach is my laboratory's work with AZD6244, a MEK inhibitor. My laboratory demonstrated the therapeutic potential of MEK inhibition as a radiation sensitizer in several cancers both in vitro and in vivo,(12) evaluated the impact of concurrent chemotherapy on the radiosensitizing effect of MEK inhibition,(13) identified biomarkers that may predict efficacy of this approach, and highlighted the mechanisms of radiation sensitization when this pathway is targeted.(12-14) This work culminated in the initiation of a CTEP sponsored Phase I trial at the NCI investigating MEK inhibition combined with the current standard chemoradiotherapy in the neoadjuvant setting in patients with locally advanced rectal cancer. There are currently three open and two completed Phase I clinical trials evaluating MEK inhibition combined with radiation and chemotherapy for the treatment of localized cancers. We have recently identified additional compounds that show preliminary efficacy in vitro as radiation sensitizers. The approach we have used in the past to select agents for study has been effective in identifying radiation sensitizers. However, this approach is evolving as we collect tumor tissue and clinical outcomes data from prostate cancer patients on my protocol, 13-C-0119. This clinical trial will allow us to evaluate multiple biologic, clinical, and radiographic predictors of local failure in patients treated with radiotherapy for localized prostate cancer. Patients enrolled in this study undergo a pretreatment multiparametric MRI and MRI-guided research biopsy of all tumors within their prostate. Following radiation therapy, patients with a rising PSA who meet biochemical failure criteria undergo repeat multiparametric MRI of the prostate and repeat MRI-guided research biopsy of persistent tumor. The molecular characteristics of tumor are analyzed to evaluate for predictors of failure and to study tumor evolution after radiation. Data from the tissue studies described above will be mined to generate a list of candidate pathway responsible for radiation resistance in prostate cancer. These data will inform laboratory studies aimed at determining the importance of these pathways in radiation response.