Bcl-2 as a Biomarker for Prognosis and Therapy of Head and Neck Cancer

描述(申请人提供)：口咽鳞状细胞癌(OPSCC)，与其他头颈部亚型不同，由于人类乳头瘤病毒(HPV)感染，其发病率以每年3-4%的速度增加。在以铂为基础的同步放化疗(白金CRT)后，HPV(+)患者的预后好于HPV(-)患者。然而，预后良好的HPV(-)和预后不良的HPV(+)OPSCC都会发生。目前确定预后良好的患者以测试非强化治疗是基于临床对诱导化疗的反应，以及与其相关的风险和明确的治疗延迟。更好的肿瘤相关客观生物标志物将更好地将患者与有效的治疗相匹配，无论是对高复发风险的患者进行强化治疗，还是对预后较好的患者进行非强化治疗的研究。我们最近发现，抗凋亡蛋白Bcl2的高表达是接受白金CRT治疗的OPSCC患者预后较差的标志，与HPV状态无关。我们确定了两组结果高度一致的患者：几乎所有患有Bcl2(-)/HPV(+)肿瘤的OPSCC患者在接受白金CRT后都能治愈，而Bcl2(+)/HPV(-)肿瘤的效果一致很差。该项目采取了几个关键步骤，将根据Bcl2表达和HPV状态对OPSCC进行分类的方法应用于临床实践。我们将在400名新出现的患者中前瞻性地验证这一分类，提高对相关风险的估计。为了加强对中期预后病例的分类，我们将探索与bcl2治疗耐药功能相关的两个生物标志物。首先，我们将首次使用BH3图谱技术，这是一种成熟的评估Bcl2功能状态的方法，作为OPSCC的生物标志物。我们预测，在免疫组织化学分类为Bcl2(+)的OPSCC中，Bcl2的功能状态将解释铂类CRT术后结果的差异。第二，Bcl2与P53抑癌基因以几种方式相互作用，表明P53功能缺失突变将补充Bcl2表达的生物标记物。我们预测，P53突变状态将改善我们的中期预后患者分为高风险和低风险两个亚组。我们还将在基于来自Bcl2(+)OPSCC的异种移植的体内临床前模型中，通过确定BH3特征是否预测对当前治疗中使用的顺铂和小分子Bcl2抑制剂ABT-737的异种移植反应，来检验我们关于Bcl2在治疗耐药中的作用的假设。高水平的Bcl2与OPSCC对铂类CRT的治疗耐药相关，为未来用Bcl2抑制剂进行定向治疗提供了一个有希望的靶点。该项目将根据与bcl2功能状态和治疗耐药机制相关的生物标记物，根据预期结果改进OPSCC的分类。因此，它将支持为高危人群开发强化治疗，为低风险人群开发发病率较低的治疗方案。

DESCRIPTION (provided by applicant): Oropharyngeal squamous cell carcinoma (OPSCC), unlike other head and neck subsites, is increasing in incidence at 3-4% per year due to human papillomavirus (HPV) infection. After platinum-based concurrent chemoradiation therapy (platinum CRT), a current standard of care having significant morbidity, HPV(+) cases have better prognosis than HPV(-) cases. Nevertheless, both good-outcome HPV(-) and poor-outcome HPV(+) OPSCC occur. Current identification of good-prognosis patients for testing de-intensified treatments is based on clinical response to induction chemotherapy, with its associated risks and definitive treatment delay. Better tumor-associated objective biomarkers would be preferable for matching patients to effective treatments, whether intensified treatment for those at high risk of recurrence or studies of de-intensified treatment for those with better prognosis. We recently identified high expression of the anti-apoptotic protein Bcl2 as a marker of worse outcome for OPSCC patients treated with platinum CRT, independent of HPV status. We identified two groups with highly uniform outcomes: almost all OPSCC patients with Bcl2(-)/HPV(+) tumors are cured following platinum CRT, while Bcl2(+)/HPV(-) tumors uniformly do poorly. This project takes several crucial steps toward bringing categorization of OPSCC by Bcl2 expression and HPV status into clinical practice. We will prospectively validate this classification on 400 newly presenting patients, sharpening the estimates of the associated hazards. To enhance the classification of intermediate-prognosis cases, we will explore two biomarkers related to the treatment resistance function of Bcl2. First, we will use BH3 profiling technology, an established method to assess Bcl2 functional status, for the first time as a biomarker in OPSCC. We predict that Bcl2 functional status will explain outcome differences following platinum CRT among OPSCC classified as Bcl2(+) by immunohistochemistry. Second, Bcl2 interacts with the p53 tumor suppressor in several ways, suggesting that loss-of-function mutations in p53 will complement the Bcl2 expression biomarker. We predict that p53 mutational status will improve the classification of our intermediate- prognosis patients into high- and low-risk subsets. We will also test our hypothesis about the function of Bcl2 in treatment resistance, in an in vivo preclinical model based on xenografts derived from Bcl2(+) OPSCC, by determining whether BH3 profiling predicts xenograft response to the cisplatin used in current therapy and to the small-molecule Bcl2 inhibitor ABT-737. The high levels of Bcl2 associated with treatment resistance of OPSCC to platinum CRT provide a promising target for future directed therapy with Bcl2 inhibitors. This project will improve classification of OPSCC with respect to expected outcomes, based on biomarkers related to Bcl2 functional status and mechanisms of treatment resistance. It thus will support development of intensified treatments for those at high risk and of treatments with less morbidity for those at low risk.