PREDICTING RESPONSE TO THERAPY: DETECTION OF ORAL CANCER

头颈部肿瘤学的一个关键研究目标是确定化疗加放疗方案的使用，以保护器官和保持生活质量。由于一些肿瘤对化疗和放射治疗无效，以及缺乏识别那些可能有反应的预测性标记物，进展受到限制。此外，当补救治疗方案的有效性有限时，持续性或复发性疾病往往被发现得较晚。口腔癌是一种毁灭性的疾病，需要更好的治疗方法。手术在一些患者中是有效的，但手术缺陷在功能和美观上是不可接受的，许多患者在手术后复发。因此，需要开发预测标记物来选择患者进行适当的治疗。我们的初步结果表明，P53的表达或突变以及凋亡抑制蛋白Bcl2和Bclx的表达相互作用，决定了对化疗的反应。我们建议确定口腔癌患者的化疗反应、器官保护和/或生存期是否由P53的过度表达和基因突变来预测，我们将确定这一点如何受到Bcl2和Bclx表达的影响。我们初步的体内和体外数据支持这样的概念，即突变的p53的肿瘤对基于顺铂的化疗方案敏感，而携带野生型p53的肿瘤对顺铂耐药。我们将在保留器官治疗前后从患者身上获得的肿瘤样本中测试我们的假设，并使用已知P53和Bcl2/Bclx状态的细胞系进行体外实验来验证这些假设。接受常规治疗的患者的样本也将进行测试，以确定在没有器官保留程序的情况下，这些基因的表达和突变可能会如何影响预后。此外，我们的初步数据表明，头颈癌患者血清中P53抗体的存在和持久性与不良预后有关。然而，我们也观察到，在成功治疗后，抗体消失，并可能复发重新出现。因此，我们计划调查P53抗体作为持续、复发和成功治疗的预测标记物的价值，并将P53抗体数据与P53突变数据相关联。这项工作中开发的信息应该会导致新的试验，使用预测标记物来选择最合适和最有效的口腔癌治疗方法。这一点，加上对早期复发的密切监测，应该反过来又能提高总体存活率。

A critical research goal in head and neck oncology is to define the use of chemotherapy plus radiation regimens that allow organ preservation and preserve quality of life. Progress has been limited by the failure of some tumors to respond to chemoradiation, and the lack of predictive markers for identifying those likely to respond. Furthermore, persistent or recurrent disease is often detected late when the effectiveness of salvage treatment options is limited. Oral cancer is a devastating disease for which better therapies are needed. Surgery is effective in some patients but the surgical defects can be functionally and cosmetically unacceptable and many patients recur after surgery. Thus, the development of predictive markers to select patients for appropriate therapy is needed. Our preliminary results suggest that p53 expression or mutation and expression of the apoptosis-blocking proteins, Bcl-2 and Bcl-x, interact to determine responsiveness to chemoradiation. We propose to determine in patients with oral cancers whether chemotherapy response, organ preservation and/or survival is predicted by p53 overexpression and gene mutation, and we will determine how this is influenced by the expression of Bcl-2 and Bcl-x. Our preliminary in vivo and in vitro data support the concept that tumors with mutant p53 are susceptible to cisplatin-based chemotherapy regimens but that those with wild type p53 are resistant. We will test our hypotheses in tumor samples obtained from patients before and after organ sparing therapy and we will test these hypotheses with in vitro experiments using cell lines with known p53 and Bcl-2/Bcl-x status. Specimens from patients undergoing conventional treatment will also be tested to determine how expression and mutation of these genes may influence outcome in the absence of organ sparing procedures. Furthermore, our preliminary data indicate that the presence and persistence of serum antibodies to p53 in patients with head and neck cancer is associated with poor outcome. However, we have also observed that following successful treatment the antibodies disappear and may reappear with relapse. Thus, we plan to investigate the value of antibodies to p53 as a predictive marker for persistence, recurrence, and successful therapy as well as to correlate p53 antibody data with p53 mutation data. The information developed in this work should result in new trials that employ predictive markers to select the most appropriate and effective treatment for oral cancer. This together with close monitoring for early recurrence should in turn lead to improved overall survival.