Mesothelin as a biomarker for clinical management of esophageal adenocarcinoma

描述（由申请人提供）：一项评价间皮素作为食管腺癌（EAC）患者临床管理生物标志物的前瞻性临床试验食管腺癌（EAC）的发病率正以每年8%的速度上升。大多数EAC患者处于晚期疾病，总体5年生存率为10%。在存在潜在可治愈疾病的患者中，大多数已经患有局部区域晚期疾病。尽管联合治疗是目前治疗局部晚期疾病的标准治疗，可提高生存率，但缺乏对肿瘤负荷和治疗反应的准确临床评价是及时选择适当治疗的重大限制。尽管有放射学和内窥镜成像，但在手术时发现四分之一假定为早期疾病的患者具有更广泛的疾病（T3或N1）。这些患者将受益于多模式治疗。在接受新辅助疗法治疗局部晚期疾病的患者中，对治疗反应的评估仍然不准确。识别和验证反映肿瘤负荷、治疗反应和复发的生物标志物对于EAC患者的临床管理和临床试验将具有高度价值。 在这项研究中，基于我们有希望的回顾性数据，我们的目标是研究血清和组织间皮素作为生物标志物，以改善EAC患者的临床管理。间皮素是细胞表面肿瘤分化抗原，其N-末端被切割并分泌到血液中，测量为血清可溶性间皮素相关肽（SMRP）。在间皮瘤、胰腺癌和卵巢癌患者中证实SMRP水平升高。最近的出版物表明，SMRP水平与间皮瘤患者的肿瘤负荷，治疗反应和预后相关。我们建议：具体目标1：前瞻性评价血清SMRP水平是否与手术切除EAC患者的（a）临床分期、（B）新辅助治疗应答和（c）疾病复发相关。具体目标二：前瞻性研究组织间皮素表达（a）放化疗前是否是治疗反应差的预测因子，（B）切除术后是否是生存差的预测因子。这种精心设计的前瞻性提案的新奇和影响超出了生物标志物研究，在测试间皮素作为巴雷特转化为EAC的标志物的效用方面;它立即被应用于临床。 使15，000名EAC患者受益。 公共卫生相关性：一个简单的预测工具，以确定早期食管腺癌患者的治疗反应差和复发的风险较高;因此，最有可能的候选人选择的治疗方式或积极的监测将受益。在这项研究中，基于我们有希望的回顾性数据，我们的目的是研究血清和组织间皮素作为生物标志物，以改善食管腺癌患者的临床管理。

DESCRIPTION (provided by applicant): A Prospective Clinical Trial to Evaluate Mesothelin as a Biomarker for the Clinical Management of Esophageal Adenocarcinoma (EAC) Patients The incidence of esophageal adenocarcinoma (EAC) is rising at an annual rate of 8%. Most EAC patients present at an advanced stage disease with an overall 5-year survival rate of 10%. Of the patients who present with potentially curable disease, majority will already have local-regional advanced disease. Although combined modality treatment, the current standard of care for locally advanced disease, improves survival, lack of accurate clinical evaluation of tumor burden and treatment response is a significant limitation in selecting appropriate treatment in a timely fashion. In spite of the radiographic and endoscopic imaging, one in four patients with a presumed early-stage disease are found to have more extensive disease (T3 or N1) at the time of surgery. These patients would have benefited from multimodality therapy. In patients treated with neo- adjuvant therapy for local-regional advanced disease, assessment of therapy response remains inaccurate. Identification and validation of a biomarker that reflects tumor burden, therapy response, and recurrence will be highly valuable for the clinical management and clinical trials of EAC patients. In this research proposal, based on our promising retrospective data, we aim to investigate serum and tissue mesothelin as a biomarker to improve the clinical management of EAC patients. Mesothelin is a cell surface tumor-differentiation antigen, the N-terminal of which is cleaved and secreted into blood, measured as serum soluble mesothelin-related peptide (SMRP). Increased SMRP levels are demonstrated in mesothelioma, pancreatic and ovarian cancer patients. Recent publications have demonstrated that the level of SMRP correlates with tumor load, therapy response, and prognosis in mesothelioma patients. We propose: Specific Aim 1: To prospectively evaluate whether serum SMRP levels correlate with (a) clinical staging, (b) response to neo-adjuvant therapy, and (c) disease recurrence in surgically resected EAC patients. Specific Aim 2: To prospectively investigate whether tissue mesothelin expression (a) pre chemo-radiation therapy is a predictor of poor therapy response, and (b) post-resection is a predictor of poor survival. The novelty and impact of this carefully designed prospective proposal extends beyond biomarker study in testing the utility of mesothelin as a marker of Barrett's transformation to EAC; it is immediately translational to benefit 15,000 patients with EAC. PUBLIC HEALTH RELEVANCE: A simple predictive instrument to identify early-stage esophageal adenocarcinoma patients at higher risk for poor therapy response and recurrence; therefore the most likely candidates for selection of therapeutic modality or aggressive surveillance will benefit. In this research proposal, based on our promising retrospective data, we aim to investigate serum and tissue mesothelin as a biomarker to improve the clinical management of esophageal adenocarcinoma patients.