Integration of EGFR Inhibitors with Radiochemotherapy

局部晚期头颈癌的器官保留治疗的发展 治疗的范例。十年前，我们制定了选择患者的策略， 根据其对单周期化疗的反应，可以选择放化疗或喉切除术。这 该方法的3年病因特异性生存率和喉保留率分别为87%和70%， 分别然而，放化疗与粘膜炎和吞咽困难的发生率增加有关 与单纯放疗相比。该应用程序的长期目标是保持高的 西妥昔单抗替代放疗，保留喉功能，同时降低治疗毒性 选择受益于这种方法的患者进行放化疗。这些目标将是 通过三个具体目标实现。具体目标一是降低保喉手术的毒副反应 在适当选择的患者中，使用西妥昔单抗-放疗代替放化疗。 在目标1A中，我们建议在西妥昔单抗放射治疗患者的II期研究中扩展我们目前的策略。 那些以前接受过放化疗的人：那些对化疗周期有反应的人。在Aim中 1B，我们建议评估对一个化疗周期有反应的患者的肿瘤活检， 接受西妥昔单抗治疗EGFR活化和下游抑制标志物作为可能的预测因子 对西妥昔单抗辐射的反应。具体目标2是研究已建立的标记物的潜力 (Aim目的2A）和通过评估磷酸化蛋白质组来发现潜在的新生物标志物（目的2B）， 预测西妥昔单抗联合放疗的反应。我们的初步数据表明， 以及确定的标志物如总EGFR、pEGFR、pSTATS、Bcl-XL和Ki 67的降低持续时间 与对EGFR抑制剂和放射的组合的反应相关。为此，我们建议 将这些研究扩展到总共20个头颈部异种移植物，10个有反应，10个无反应。在 目的2B我们将使用蛋白质组学技术评估西妥昔单抗辐射对磷蛋白的影响。 我们的初步数据表明，这是一个有前途的方法，确定新的磷蛋白， 受西妥昔单抗治疗的影响。具体目标3是进行临床前研究，以改善 用放射化学疗法抑制EGFR的功效。在目标3A中，我们关注的是 EGFR抑制与放化疗联合治疗的方案。在Aim 3B中，我们将专注于一部小说 通过HSP 90抑制靶向EGFR的方法。我们的初步数据显示格尔德霉素， 热休克蛋白90的抑制剂，加速顺铂耐药细胞中EGFR的降解，导致细胞 毒性和放射增敏作用。我们认为我们的临床前和临床团队在以下方面有着广泛的记录： 这一领域使得这些研究有可能改善患者的结果。

The development of organ-conserving treatment for locally advanced head and neck cancers shifted the paradigm for treatment. A decade ago, we developed the strategy of selecting patients for chemoradiotherapy or for laryngectomy based on their response to a single cycle of chemotherapy. This approach results in 3-year cause-specific survival and laryngeal preservation rates of 87% and 70%, respectively. However, chemoradiation is associated with an increased rate of mucositis and dysphagia compared with radiotherapy alone. The long-term goal of this application is to preserve a high rate of larynx preservation while decreasing the toxicity of treatment by using cetuximab-radiation instead of chemoradiotherapy in patients selected to benefit from this approach. These goals will be achieved through 3 specific aims. Specific Aim 1 is to decrease the toxicity of larynx-preserving treatment by using cetuximab-radiation in place of chemoradiation in appropriately selected patients. In Aim 1A we propose to extend our current strategy in a phase II study of cetuximab-radiation for patients who would previously have received chemoradiation: those responding to a cycle of chemotherapy. In Aim 1B, we propose to assess tumor biopsies in the patients who respond to a cycle of chemotherapy and then receive cetuximab for markers of EGFR activation and downstream inhibition as possible predictors of response to cetuximab-radiation. Specific Aim 2 is to investigate the potential of established markers (Aim 2A) and to discover potential new biomarkers (Aim 2B) by assessment of phosphoproteome to predict response to cetuximab combined with radiation. Our preliminary data suggest that the extent and duration of decrease in the established markers like total EGFR, pEGFR, pSTATS, Bcl-XL, and Ki67 correlate with response to the combination of EGFR inhibitors and radiation. In this aim, we propose to extend these studies to a total of 20 head and neck xenografts, 10 responsive and 10 non-responsive. In Aim 2B we will assess the effects of cetuximab-radiation on phosphoproteins using proteomic technology. Our preliminary data indicate that this is a promising method of identifying novel phosphoproteins that are affected by cetuximab treatment. Specific Aim 3 is to carry out preclinical studies to improve the efficacy of EGFR inhibition with radiochemotherapy. In Aim 3A, we focus on the potential importance of schedule for combining EGFR inhibition with radiochemotherapy. In Aim 3B we will focus on a novel approach toward targeting EGFR via HSP90 inhibition. Our preliminary data show that geldanamycin, an inhibitor of HSP90, accelerates the degradation of EGFR in cisplatin resistant cells, leading to both cellular toxicity and radiosensitization. We feel our preclinical and clinical team with an extensive track record in this field makes it likely that these studies will improve patient outcome.