Targeting mechanisms of radiation resistance

这种方法的一个例子是我的实验室对AZD 6244（一种MEK抑制剂）的研究。我的实验室在体外和体内证明了MEK抑制作为几种癌症的放射增敏剂的治疗潜力，（12）评价了同步化疗对MEK抑制的放射增敏作用的影响，（13）确定了可能预测这种方法疗效的生物标志物，并强调了靶向该途径时的放射增敏机制。（12-14）这项工作最终在NCI启动了CTEP申办的I期试验，研究MEK抑制联合当前标准放化疗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抑制与放射和化疗联合治疗局部癌症。我们最近已经鉴定了另外的化合物，其在体外显示出作为辐射增敏剂的初步功效。我们过去用于选择研究药物的方法在识别辐射增敏剂方面是有效的。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局数据，这种方法正在发展。这项临床试验将使我们能够评估多个生物学，临床和放射学预测局部失败的患者接受放射治疗的局限性前列腺癌。入组本研究的患者接受治疗前多参数MRI和MRI引导的前列腺内所有肿瘤的研究活检。放射治疗后，PSA升高且符合生化失败标准的患者接受前列腺重复多参数MRI检查，并对持续性肿瘤重复MRI引导的研究性活检。同时处理肿瘤的DNA和RNA，并收集匹配的标本用于诊断目的。计划的分析包括肿瘤中的全外显子组测序，以与体细胞DNA进行比较，拷贝数分析，以及肿瘤中的微阵列，以评估失败的预测因素并研究放射后的肿瘤演变。来自上述组织研究的数据将被挖掘以生成负责前列腺癌中的辐射抗性的候选途径的列表。这些数据将为旨在确定这些途径在辐射反应中的重要性以及抑制这些途径的影响的实验室研究提供信息。预计将鉴定出许多候选突变和途径。将优先考虑那些在前列腺癌和辐射反应的背景下是新的，以及那些有可用的靶向药物。

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. Tumor is processed simultaneously for DNA and RNA, with matched specimens collected for diagnostic purposes. Planned analyses include whole exome sequencing in tumor to compare to somatic DNA, copy number analysis, and microarray in tumor 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 and the effects of inhibiting these pathways. It is anticipated that a number of candidate mutations and pathways will be identified. Priority will be given to those that are novel in the context of prostate cancer and radiation response, and those with available agents for targeting.