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

Bcl-2 作为头颈癌预后和治疗的生物标志物

• 批准号: 8705631
• 负责人: JAMES W ROCCO
• 金额: $ 12.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705631
• 关键词: Accounting; Adverse effects; Apoptotic; BCL2 gene; Back; Binding; Biochemical Markers; Biological Markers; Cisplatin; Classification; Clinical; Clinical Treatment; Clinical Trials; Clinical Trials Design; Complement; Cytotoxic Chemotherapy; Development; Disease; Epidemic; Future; Genomics; Grant; Head and Neck Cancer; Head and neck structure; Human Papillomavirus; Human papilloma virus infection; Immunohistochemistry; Incidence; Individual; Infection; Lead; Methods; Morbidity - disease rate; Mutation; Oropharyngeal; Oropharyngeal Squamous Cell Carcinoma; Outcome; Patients; Pharyngeal structure; Platinum; Population; Pre-Clinical Model; Prognostic Marker; Protein p53; Proteins; Recurrence; Resistance; Risk; Risk Factors; Site; Smoking; Specimen; Staging; Staining method; Stains; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tonsil; Xenograft Model; Xenograft procedure; base; chemoradiation; chemotherapy; clinical practice; cohort; design; drinking; effective therapy; functional status; hazard; high risk; improved; in vivo; in vivo Model; inhibitor/antagonist; loss of function mutation; new technology; new therapeutic target; novel; outcome forecast; pre-clinical; pro-apoptotic protein; prospective; response; small molecule; standard care; standard of care; tool; tumor

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.

描述（由申请人提供）：口咽鳞状细胞癌（OPSCC）与其他头颈部亚部位不同，由于人乳头瘤病毒（HPV）感染，其发病率每年增加3-4%。在铂基同步放化疗（铂CRT）后，目前的标准治疗具有显著的发病率，HPV（+）病例的预后优于HPV（-）病例。然而，好结果的HPV（-）和差结果的HPV（+）OPSCC都发生。目前，用于检测去强化治疗的预后良好患者的鉴定是基于对诱导化疗的临床反应及其相关风险和明确的治疗延迟。更好的肿瘤相关客观生物标志物对于匹配患者有效治疗是优选的，无论是针对复发高风险患者的强化治疗还是针对预后较好患者的去强化治疗研究。 我们最近发现抗凋亡蛋白Bcl 2的高表达是铂类CRT治疗OPSCC患者预后不良的标志，与HPV状态无关。我们确定了两组具有高度一致的结局：几乎所有Bcl 2（-）/HPV（+）肿瘤的OPSCC患者在铂CRT后均治愈，而Bcl 2（+）/HPV（-）肿瘤均表现不佳。 该项目采取了几个关键步骤，将Bcl 2表达和HPV状态的OPSCC分类纳入临床实践。我们将对400名新出现的患者进行前瞻性验证，以提高相关危害的估计值。为了提高中预后病例的分类，我们将探索与Bcl 2的治疗抵抗功能相关的两个生物标志物。首先，我们将使用BH 3分析技术，一种评估Bcl 2功能状态的既定方法，首次作为OPSCC的生物标志物。我们预测，Bcl 2功能状态将解释免疫组织化学分类为Bcl 2（+）的OPSCC中铂类CRT后的结局差异。其次，Bcl 2与p53肿瘤抑制因子以几种方式相互作用，表明p53中的功能丧失突变将补充Bcl 2表达生物标志物。我们预测，p53突变状态将改善我们的中等预后患者的分类为高风险和低风险的子集。我们还将在基于来自Bcl 2（+）OPSCC的异种移植物的体内临床前模型中，通过确定BH 3谱是否预测异种移植物对当前治疗中使用的顺铂和对小分子Bcl 2抑制剂ABT-737的反应，来检验我们关于Bcl 2在治疗抗性中的功能的假设。与OPSCC对铂CRT的治疗抗性相关的高水平Bcl 2为未来使用Bcl 2抑制剂的定向治疗提供了有希望的靶点。 该项目将根据与Bcl 2功能状态和治疗抗性机制相关的生物标志物，在预期结果方面改进OPSCC的分类。因此，它将支持为高风险患者开发强化治疗，为低风险患者开发发病率较低的治疗。