A critical research chemoradiation, and the lack of predictive markers for identifying those likely to respond. Advanced laryngeal cancer is a devastating disease for which better therapies are needed. Surgery is effective in some patients but the surgical defects can be functionally and cosmetically unacceptable and many patients recur after surgery. Thus, the development of predictive markers to select patients for appropriate therapy is needed. Our preliminary results suggest that p53 expression or mutation and expression of the apoptosis-blocking proteins, BCL-2 and BCL-xL, interact to determine responsiveness to chemoradiation. We propose to determine in patients with advanced laryngeal cancer treated on the multi-institutional, randomized Department of Veterans Affairs Laryngeal Cancer Study whether chemotherapy response, organ preservation and/or survival is predicted by p53 overexpression and gene mutation, and we will determine how this is influenced by the expression of BCL-2 and BCL-xL. Our preliminary in vivo and in vitro data support the concept that tumors with mutant p53 are susceptible to cisplatin-based chemotherapy regimens but that those with wild type p53 are resistant. We will test our hypotheses in tumor samples obtained from patients before and after organ-sparing therapy and we will test these hypotheses with in-vitro experiments using cell lines with known p53 and BCL-2/BCL-xL status. The mechanism of cell death (apoptosis-dependent or independent) may determine the efficacy of different interventions and dictate which treatments are appropriate. The information acquired in this work should result in new trials that employ predictive markers to select the most appropriate and effective treatment for advanced laryngeal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083087-04
Application #
6514176
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Tricoli, James
Project Start
1999-09-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$234,264
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Brenner, J Chad; Graham, Martin P; Kumar, Bhavna et al. (2010) Genotyping of 73 UM-SCC head and neck squamous cell carcinoma cell lines. Head Neck 32:417-26
Kumar, Bhavna; Cordell, Kitrina G; Lee, Julia S et al. (2008) EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 26:3128-37
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Kumar, Bhavna; Cordell, Kitrina G; D'Silva, Nisha et al. (2008) Expression of p53 and Bcl-xL as predictive markers for larynx preservation in advanced laryngeal cancer. Arch Otolaryngol Head Neck Surg 134:363-9
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Kumar, Bhavna; Cordell, Kitrina G; Lee, Julia S et al. (2007) Response to therapy and outcomes in oropharyngeal cancer are associated with biomarkers including human papillomavirus, epidermal growth factor receptor, gender, and smoking. Int J Radiat Oncol Biol Phys 69:S109-11
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Verhaegen, Monique; Bauer, Joshua A; Martin de la Vega, Cristina et al. (2006) A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species. Cancer Res 66:11348-59

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