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

描述（由申请人提供）：口咽鳞状细胞癌（OPSCC）与其他头颈部亚位点不同，由于人乳头瘤病毒（HPV）感染，其发病率每年增加3-4%。在以铂为基础的同步放化疗（铂CRT）后，HPV（+）病例的预后比HPV（-）病例好。然而，结果良好的HPV（-）和结果较差的HPV(+) OPSCC都有发生。目前对预后良好的患者进行去强化治疗的鉴定是基于对诱导化疗的临床反应，以及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有利于患者与有效的治疗相匹配，无论是对复发高风险患者的强化治疗，还是对预后较好的患者进行去强化治疗的研究。我们最近发现抗凋亡蛋白Bcl2的高表达是接受铂类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：几乎所有伴有Bcl2(-)/HPV（+）肿瘤的OPSCC患者在铂类CRT治疗后都治愈了，而Bcl2(+)/HPV（-）肿瘤的治疗效果都很差。该项目为通过Bcl2表达和HPV状态将OPSCC分类纳入临床实践采取了几个关键步骤。我们将在400名新出现的患者中前瞻性地验证这一分类，强化相关危险的估计。为了加强对中度预后病例的分类，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，我们将使用BH3分析技术，这是一种评估Bcl2功能状态的既定方法，首次作为OPSCC的生物标志物。我们预测Bcl2功能状态将解释经免疫组织化学分类为Bcl2（+）的OPSCC在铂类CRT后的结果差异。其次，Bcl2以多种方式与p53肿瘤抑制因子相互作用，这表明p53的功能缺失突变将补充Bcl2表达的生物标志物。我们预测p53突变状态将改善我们的中预后患者分为高风险和低风险亚群的分类。我们还将在基于Bcl2(+) OPSCC的异种移植物的体内临床前模型中验证我们关于Bcl2在治疗耐药中的功能的假设，通过确定BH3谱分析是否预测异种移植物对当前治疗中使用的顺铂和小分子Bcl2抑制剂ABT-737的反应。高水平的Bcl2与OPSCC对铂CRT治疗耐药相关，为未来Bcl2抑制剂的定向治疗提供了一个有希望的靶点。该项目将基于与Bcl2功能状态和治疗耐药机制相关的生物标志物，根据预期结果改进OPSCC的分类。因此，它将支持开发针对高危人群的强化治疗方法，以及针对低风险人群的低发病率治疗方法。

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.