Tumor hypoxia has been shown to decrease tumor control and survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy. With the development of therapies targeted against hypoxia such as Tirapazamine (TPZ) and HIF-1oc inhibitors, there is a need for a simple and non- invasive way to identify patients who would benefit from such treatments. Presently, the most widely accepted method for detecting tumor hypoxia is the Eppendorf pO;. histograph, which is an invasive technique that requires a high level of patient cooperation. In addition, it cannot be used for deeply seated tumors. We have recently shown that Osteopontin (OPN), a secreted protein, whose expression can be measured in patient blood via a simple ELISA test, can be used as a surrogate marker for tumor hypoxia in a small group of HNSCC patients treated with chemoradiotherapy. Plasma OPN level correlated not only with tumor pO2 measurements but also with treatment outcomes (freedom from relapse and overall survival). The HeadSTART trial, which is an international phase III randomized trial evaluating the effectiveness of adding TPZ, a hypoxic cytotoxin, to conventional chemoradiotherapy in patients with advanced HNSCC provides a unique opportunity to validate the role of OPN as a secreted hypoxia marker. In this study, 850 HNSCC patients are randomized to concomitant radiation, cisplatin and TPZ versus concomitant radiation and cisplatin alone. Pretreatment plasma samples of these patients will be analyzed for OPN levels using an optimized ELISA system and compared to treatment outcomes in terms of failure-free survival and overall survival. If OPN is indeed a secreted marker for tumor hypoxia, the addition of TPZ would be predicted to benefit only those patients with elevated pretreatment OPN. Similarly, the elimination of hypoxic tumor cells by TPZ will diminish the prognostic impact of OPN in the experimental arm when compared to the control (non-TPZ) arm. We plan to correlate the expression of OPN with tumor expression of 4 known tissue makers for hypoxia (HIF-1cc, VEGF, CA IX and Glut-1) and 2 novel markers (Galectin-1 and Ephrin A1). We will also correlate plasma OPN levels with tumor hypoxia that is determined from pretreatment [18]Fluoroazomicin- arabinofuranoside (18FAZA) PET scans in a subset of patients. Correlation of OPN to hypoxia-specific PET scans and tissue markers will provide 2 different approaches to validate OPN as secreted hypoxia markers in HNSCC. As a secondary objective, we will study the expression and prognostic impact of 3 other potential secreted markers for hypoxia, which are plasma VEGF, IL-8 and CTGF. In addition, we will explore the use of MALDI-ToF proteomic and several sophisticated statistical softwares to identify a global proteomic signature for predicting relapse in patients treated with and without TPZ. We will also conduct proteomic analysis of serial plasma samples obtained from the same patients before and after TPZ to identify novel hypoxia-related secreted proteins that can server as future biomarkers and targets for new therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118582-05
Application #
7768470
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Kim, Kelly Y
Project Start
2006-04-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$376,458
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Graves, Edward E; Hicks, Rodney J; Binns, David et al. (2016) Quantitative and qualitative analysis of [(18)F]FDG and [(18)F]FAZA positron emission tomography of head and neck cancers and associations with HPV status and treatment outcome. Eur J Nucl Med Mol Imaging 43:617-25
Mills, Anne M; Beck, Andrew H; Pourmand, Nader et al. (2012) Evaluation of ProExC as a prognostic marker in oropharyngeal squamous cell carcinomas. Am J Surg Pathol 36:1158-64
Cao, Hongbin; Banh, Alice; Kwok, Shirley et al. (2012) Quantitation of human papillomavirus DNA in plasma of oropharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 82:e351-8
Le, Quynh-Thu; Fisher, Richard; Oliner, Kelly S et al. (2012) Prognostic and predictive significance of plasma HGF and IL-8 in a phase III trial of chemoradiation with or without tirapazamine in locoregionally advanced head and neck cancer. Clin Cancer Res 18:1798-807
Tang, Chad; Murphy, James D; Khong, Brian et al. (2012) Validation that metabolic tumor volume predicts outcome in head-and-neck cancer. Int J Radiat Oncol Biol Phys 83:1514-20
Chu, Karen P; Murphy, James D; La, Trang H et al. (2012) Prognostic value of metabolic tumor volume and velocity in predicting head-and-neck cancer outcomes. Int J Radiat Oncol Biol Phys 83:1521-7
Lim, Annette M; Rischin, Danny; Fisher, Richard et al. (2012) Prognostic significance of plasma osteopontin in patients with locoregionally advanced head and neck squamous cell carcinoma treated on TROG 02.02 phase III trial. Clin Cancer Res 18:301-7
Chu, Karen P; Shema, Sarah; Wu, Simon et al. (2011) Head and neck cancer-specific survival based on socioeconomic status in Asians and Pacific Islanders. Cancer 117:1935-45
Banh, Alice; Zhang, Jing; Cao, Hongbin et al. (2011) Tumor galectin-1 mediates tumor growth and metastasis through regulation of T-cell apoptosis. Cancer Res 71:4423-31
Murphy, James D; Chisholm, Karen M; Daly, Megan E et al. (2011) Correlation between metabolic tumor volume and pathologic tumor volume in squamous cell carcinoma of the oral cavity. Radiother Oncol 101:356-61

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