The candidates long-term objective is to become an independent investigator, focusing on the use of biological markers to guide and improve the treatment of patients with gastrointestinal malignancies. In this proposal, he plans to perform a molecular analysis of survival in a large, prospectively collected cohort of patients with esophageal cancer. Under the mentorship of David Christiani, MD, the candidate will achieve the specific aims of examining the association between overall survival and the presence of specific genetic polymorphisms (GSTP1, GSTM1, GSTT1, CYP1A1, CYP3A5, p53, XRCC1 and ERCC2) in patients with esophageal cancer. In addition, he will examine the association between overall survival and the expression of molecular markers (p53, p21, COX-2, VEGF, and TS) in tissue biopsy specimens from these patients. The research design makes use of a prospective cohort of over 600 patients with esophageal cancer, collected as part of a larger project undertaken by the candidate's mentor examining esophageal cancer risk factors. The methods include the collection of blood samples and clinical data from each of the patients (with patient consent). DNA extracted from each of these blood specimens will be tested for the presence of specific genetic polymorphisms. In addition, stored paraffin-embedded tissue specimens for each of the patients will be retrieved and evaluated for the expression of specific molecular markers. The presence of specific polymorphisms and tissue markers will be correlated with overall survival, after adjustment for possible confounding variables. The project has important health relatedness: in the year 2002, there will be an estimated 13,100 new cases of esophageal cancer in the United States. Among all patients who develop esophageal cancer, 12,600 (96%) will develop metastatic disease and will ultimately die from their malignancy. Recent studies have suggested that the genetic polymorphisms being examined in this study affect the metabolism of both carcinogens and agents used as systemic chemotherapy, and therefore may significantly affect prognosis. Similarly, the expression of specific molecular markers in tumor tissue may affect biologic behavior and prognosis. A better understanding of the association between genetic polymorphisms, expression of tumor molecular markers, and prognosis may lead to better treatment strategies and improved survival rates for patients with esophageal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA093401-04
Application #
7102689
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2003-07-03
Project End
2008-06-30
Budget Start
2006-08-28
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$135,837
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Kulke, Matthew H; Chan, Jennifer A; Meyerhardt, Jeffrey A et al. (2011) A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother Pharmacol 68:293-300
Chan, Jennifer A; Zhu, Andrew X; Stuart, Keith et al. (2010) Phase II study of pemetrexed in patients with advanced neuroendocrine tumors. Cancer Chemother Pharmacol 66:961-8
Strosberg, Jonathan R; Coppola, Domenico; Klimstra, David S et al. (2010) The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas 39:799-800
Kulke, Matthew H; Anthony, Lowell B; Bushnell, David L et al. (2010) NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 39:735-52
Bradbury, Penelope A; Kulke, Matthew H; Heist, Rebecca S et al. (2009) Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes. Pharmacogenet Genomics 19:613-25
Kulke, Matthew H; Hornick, Jason L; Frauenhoffer, Christine et al. (2009) O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15:338-45
Cescon, David W; Bradbury, Penelope A; Asomaning, Kofi et al. (2009) p53 Arg72Pro and MDM2 T309G polymorphisms, histology, and esophageal cancer prognosis. Clin Cancer Res 15:3103-9
Zhu, Andrew X; Clark, Jeffrey W; Ryan, David P et al. (2007) Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer. Cancer Chemother Pharmacol 59:285-93
Kulke, Matthew H (2007) Gastrointestinal neuroendocrine tumors: a role for targeted therapies? Endocr Relat Cancer 14:207-19
Kulke, Matthew H (2007) Clinical presentation and management of carcinoid tumors. Hematol Oncol Clin North Am 21:433-55;vii-viii

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