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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA164585-02
Application #
8508213
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Thurin, Magdalena
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$186,970
Indirect Cost
$84,745
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Kadota, Kyuichi; Sima, Camelia S; Arcila, Maria E et al. (2016) KRAS Mutation Is a Significant Prognostic Factor in Early-stage Lung Adenocarcinoma. Am J Surg Pathol 40:1579-1590
Mayor, Marissa; Yang, Neng; Sterman, Daniel et al. (2016) Immunotherapy for non-small cell lung cancer: current concepts and clinical trials. Eur J Cardiothorac Surg 49:1324-33
Adusumilli, Prasad S (2016) Spread through alveolar spaces: An aerogenous invasion in pulmonary adenocarcinomas. J Thorac Cardiovasc Surg 152:73-4
Yeh, Yi-Chen; Kadota, Kyuichi; Nitadori, Jun-ichi et al. (2016) International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification predicts occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma. Eur J Cardiothorac Surg 49:e9-e15
Morello, Aurore; Sadelain, Michel; Adusumilli, Prasad S (2016) Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discov 6:133-46
Buitrago, Daniel H; Patnaik, Santosh K; Kadota, Kyuichi et al. (2015) Small RNA sequencing for profiling microRNAs in long-term preserved formalin-fixed and paraffin-embedded non-small cell lung cancer tumor specimens. PLoS One 10:e0121521
Kadota, Kyuichi; Nitadori, Jun-ichi; Ujiie, Hideki et al. (2015) Prognostic Impact of Immune Microenvironment in Lung Squamous Cell Carcinoma: Tumor-Infiltrating CD10+ Neutrophil/CD20+ Lymphocyte Ratio as an Independent Prognostic Factor. J Thorac Oncol 10:1301-10
Kadota, Kyuichi; Yeh, Yi-Chen; Villena-Vargas, Jonathan et al. (2015) Tumor Budding Correlates With the Protumor Immune Microenvironment and Is an Independent Prognostic Factor for Recurrence of Stage I Lung Adenocarcinoma. Chest 148:711-21
Ujiie, Hideki; Kadota, Kyuichi; Chaft, Jamie E et al. (2015) Solid Predominant Histologic Subtype in Resected Stage I Lung Adenocarcinoma Is an Independent Predictor of Early, Extrathoracic, Multisite Recurrence and of Poor Postrecurrence Survival. J Clin Oncol 33:2877-84
Kadota, Kyuichi; Eguchi, Takashi; Villena-Vargas, Jonathan et al. (2015) Nuclear estrogen receptor-α expression is an independent predictor of recurrence in male patients with pT1aN0 lung adenocarcinomas, and correlates with regulatory T-cell infiltration. Oncotarget 6:27505-18

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