Biomarkers to Guide Treatment and Improve Survival in Oral/Oropharyngeal Cancer

指导口腔/口咽癌治疗并提高生存率的生物标志物

• 批准号: 7649662
• 负责人: THOMAS E. CAREY
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-02 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649662
• 关键词: Affect; Aftercare; Alternative Therapies; Biological Factors; Biological Markers; Biology; Biopsy; CDKN2A gene; Cancer Center; Cancer Patient; Carboplatin; Categories; Characteristics; Clinical Trials; Communication; DNA; Data; Deglutition; Development; Diagnosis; Disease; Enrollment; Epidermal Growth Factor Receptor; Genetic Status; Goals; HPV-High Risk; Head and Neck Cancer; In Vitro; In complete remission; Incidence; Individual; Intensity-Modulated Radiotherapy; Investigation; Larynx; Lead; Left; Lymphoma; Malignant Neoplasms; Medicine; Michigan; Modeling; Molecular; Morbidity - disease rate; Mouth Neoplasms; Operative Surgical Procedures; Oral; Oral cavity; Organ; Organ failure; Oropharyngeal; Oropharyngeal Neoplasms; Outcome; Paclitaxel; Patients; Pattern; Phenotype; Predictive Value; Protocols documentation; Quality of life; RNA; Radiation; Radiosurgery; Recurrence; Relapse; Resistance; Role; Site; Smell Perception; Smoking; Specimen; Staging; Survival Rate; System; TP53 gene; Taste Perception; Testing; Time; Tissue Harvesting; Tissue Microarray; Translational Research; Treatment Effectiveness; Treatment Failure; Treatment Protocols; Tumor Biology; United States National Institutes of Health; Universities; base; chemotherapy; conventional therapy; evidence base; high risk; improved; irradiation; malignant breast neoplasm; malignant mouth neoplasm; malignant oropharynx neoplasm; melanoma; neoplastic cell; non-smoker; outcome forecast; protein expression; public health relevance; receptor expression; response; therapy outcome; treatment response; treatment strategy; tumor

DESCRIPTION (provided by applicant): The NIH roadmap identifies the development of evidence-based, individualized medicine to improve survival rates and quality of life as important goals for the next decade. Oral and oropharyngeal cancer together are the 6th most common cancer worldwide. Most patients have advanced (stage III & IV) disease at the time of diagnosis and dismal 5 year survival rates that range from 0-40% depending on tumor site and stage. These survival rates are poorer than those for lymphoma, breast cancer and malignant melanoma. Conventional treatments based on radical surgery and radiation are associated with profound functional morbidity affecting communication, taste, smell, swallowing, cosmesis, sense of self, and overall quality of life. Combined chemotherapy and radiation are very effective in some patients but not others. Current data suggest that surgical treatment produces better outcome for oral cancer and worse for oropharynx, whereas many oropharynx patients have an excellent response chemotherapy and radiation whereas many with oral cavity do poorly with this treatment. In both sites, treatment failures and excess morbidity from an ineffective treatment approach indicate that it is necessary to identify and understand the molecular basis for treatment response and assign patients individually to maximize treatment effectiveness to improve survival and quality of life. The objective of this proposal is to identify biomarkers of oral and oropharyngeal cancers that predict outcome and identify the most appropriate treatment strategy. To accomplish this we will use pre- and post-treatment specimens from completed and on-going clinical trials for oral and oropharyngeal cancers and a panel of biomarkers that have already shown predictive value in oropharynx cancers treated by chemotherapy and radiation. Specifically, we will assess protein expression in tissue microarrays as well as genetic status of a panel of biomarkers. Tissue microarrays of surgical specimens from patients enrolled in surgery and radiation protocols or in organ sparing trials for which both pretreatment biopsies and surgical salvage specimens are available will be used. DNA and RNA will also be harvested from these tissues. Biomarkers will include: High risk human papilloma virus type and copy number, p53 status and expression, BCLXL expression, the epidermal growth factor receptor (EGFR), and p16. All have predictive value for response to therapy and survival in oropharynx cancers treated by induction chemotherapy and concurrent chemoradiation. We postulate that these and some additional markers to be developed can differentiate those oral cavity tumors that will respond to organ sparing and those that won't. Similarly, these markers can identify oropharynx tumors that require alternative therapy. We will use in vitro systems to analyze the functional role of biomarkers in resistance and model targeted therapy that may be effective in new clinical trials. PUBLIC HEALTH RELEVANCE: Oral and oropharyngeal cancers affect more than 500,000 people worldwide and the incidence is increasing, particularly in younger individuals and non-smokers. Most cancers at these sites are already at an advanced stage when discovered and survival is poor. Radical surgery combined with radiation to remove the tumors leaves the patient with visible and functional deficits. Organ sparing therapies have been developed based on chemotherapy and radiation but some patients fail to respond and then cannot be cured with surgery. The development of tumor biomarkers that identify those tumors best suited to organ sparing therapy and those best suited to surgery based on tumor biology should increase both survival and the quality of life of the patient. A panel of biomarkers that predict outcome has been identified and these will now be applied to oral cavity and oropharynx cancers to distinguish those most likely to respond to different therapies. The results of this investigation will lead to new treatment strategies that are individualized for each patient.

描述（由申请人提供）：NIH路线图确定了以证据为基础的个体化医学的发展，以提高生存率和生活质量，这是未来十年的重要目标。口腔癌和口咽癌是全世界第六大最常见的癌症。大多数患者在诊断时已处于晚期（III期和IV期），根据肿瘤部位和分期，5年生存率从0-40%不等。这些患者的存活率低于淋巴瘤、乳腺癌和恶性黑色素瘤患者。基于根治性手术和放疗的常规治疗与影响沟通、味觉、嗅觉、吞咽、美容、自我意识和整体生活质量的严重功能失调有关。化疗和放疗联合治疗对一些病人非常有效，但对另一些病人无效。目前的数据表明，手术治疗口腔癌的效果较好，而口咽癌的效果较差，而许多口咽癌患者对化疗和放疗的反应很好，而许多口腔患者对这种治疗的反应很差。在这两个地区，无效治疗方法导致的治疗失败和高发病率表明，有必要识别和了解治疗反应的分子基础，并对患者进行个体化分配，以最大限度地提高治疗效果，提高生存率和生活质量。本提案的目的是确定预测预后的口腔癌和口咽癌的生物标志物，并确定最合适的治疗策略。为了实现这一目标，我们将使用来自已完成和正在进行的口腔和口咽癌临床试验的治疗前和治疗后标本，以及一组生物标志物，这些生物标志物已经在经化疗和放疗治疗的口咽癌中显示出预测价值。具体来说，我们将评估组织微阵列中的蛋白质表达以及一组生物标志物的遗传状态。将使用手术和放疗方案或器官保留试验中登记的患者的手术标本的组织微阵列，其中预处理活检和手术保留标本都是可用的。DNA和RNA也将从这些组织中获取。生物标志物将包括：高危人乳头瘤病毒类型和拷贝数、p53状态和表达、BCLXL表达、表皮生长因子受体（EGFR）和p16。所有这些指标都对诱导化疗和同步放化疗治疗口咽癌的治疗反应和生存具有预测价值。我们假设这些和其他一些有待开发的标志物可以区分那些对器官保留有反应的口腔肿瘤和那些没有反应的口腔肿瘤。同样，这些标记物可以识别需要替代治疗的口咽部肿瘤。我们将使用体外系统来分析生物标志物在耐药性中的功能作用，并模拟可能在新的临床试验中有效的靶向治疗。公共卫生相关性：口腔癌和口咽癌影响全世界50多万人，发病率正在增加，特别是在年轻人和非吸烟者中。这些部位的大多数癌症在发现时已经处于晚期，生存率很低。根治性手术结合放射疗法切除肿瘤后，患者会出现明显的功能缺陷。器官保留疗法已经在化疗和放疗的基础上发展起来，但一些患者没有反应，因此无法通过手术治愈。肿瘤生物标志物的发展可以根据肿瘤生物学来确定哪些肿瘤最适合保留器官治疗，哪些肿瘤最适合手术治疗，这将提高患者的生存率和生活质量。已经确定了一组预测结果的生物标志物，这些标志物现在将应用于口腔癌和口咽癌，以区分那些最有可能对不同疗法产生反应的癌症。这项调查的结果将导致新的治疗策略，为每个病人个性化。