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: 7778358
• 负责人: THOMAS E. CAREY
• 金额: $ 34.41万
• 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/7778358
• 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; Regimen; 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(由申请者提供)：NIH路线图将发展以证据为基础的个性化药物以提高存活率和生活质量确定为下一个十年的重要目标。口腔癌和口咽癌加在一起是全球第六大常见癌症。大多数患者在确诊时已经是晚期(III和IV期)疾病，根据肿瘤部位和分期的不同，5年生存率从0-40%不等。这些存活率比淋巴瘤、乳腺癌和恶性黑色素瘤的存活率低。基于根治性手术和放射治疗的传统治疗与严重的功能障碍有关，影响沟通、味觉、嗅觉、吞咽、美容、自我感觉和整体生活质量。联合化疗和放射治疗对某些患者非常有效，但对另一些患者无效。目前的数据表明，手术治疗对口腔癌有较好的疗效，而对口咽部的效果较差，而许多口咽部患者对化疗和放疗有很好的疗效，而许多口腔患者在这种治疗下效果不佳。在这两个地点，治疗失败和无效治疗方法的过度发病率表明，有必要识别和了解治疗反应的分子基础，并对患者进行单独分配，以最大限度地提高治疗效果，以提高存活率和生活质量。这项建议的目的是确定口腔和口咽癌的生物标记物，预测结果并确定最合适的治疗策略。为了实现这一目标，我们将使用口腔和口咽癌已完成和正在进行的临床试验的治疗前和治疗后的样本，以及一组已经显示出在接受化疗和放射治疗的口咽癌中具有预测价值的生物标志物。具体地说，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。参加手术和放射治疗方案或器官保留试验的患者的手术标本的组织微阵列将被使用，在这些试验中，既可以进行预活检，也可以进行手术挽救标本。还将从这些组织中提取DNA和RNA。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。所有这些都对口咽癌诱导化疗和同步放化疗的疗效和生存率有预测价值。我们推测，这些标记物和一些有待开发的额外标记物可以区分那些对器官保留有反应的口腔肿瘤和那些不会有反应的口腔肿瘤。同样，这些标记物可以识别需要替代治疗的口咽肿瘤。我们将使用体外系统来分析生物标记物在耐药性中的功能作用，并建立可能在新的临床试验中有效的靶向治疗模型。公共卫生相关性：口腔和口咽癌影响全世界50多万人，而且发病率正在增加，特别是在年轻人和非吸烟者中。这些地方的大多数癌症在被发现时已经处于晚期，存活率很低。根治性手术结合放射切除肿瘤，会给患者留下视觉和功能上的缺陷。器官保留疗法是在化疗和放射治疗的基础上开发出来的，但一些患者没有反应，然后无法通过手术治愈。肿瘤生物标志物的开发可以识别最适合器官保留治疗的肿瘤和最适合基于肿瘤生物学的手术的肿瘤，这些肿瘤生物标志物的开发应该会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记物，这些标记物现在将应用于口腔和口咽癌，以区分哪些最有可能对不同的治疗方法有反应。这项调查的结果将导致针对每个患者的新的治疗策略。