Protocol HNS 94-001 
October 4, 1994 
Page 1 
Clinical Protocol: Modification of Tumor Suppressor 
Gene Expression In 
Head and Neck Squamous Cell Carcinoma (HNSCC) with an Adenovirus 
Vector Expressing Wlldtype p53" 
1.0 OBJECTIVES 
1.1 To determine the maximum tolerated dose of the wild-type p53 adenovirus vector in patients with 
refractory HNSCC. 
1.2 To determine the qualitative and quantitative toxicity and reversibility of toxicity of this treatment 
approach. 
1 .3 To document observed antitumor activity of this treatment approach. 
2.0 BACKGROUND AND RATIONALE 
2 . i Molecular events in HNSCC 
Head and Neck Squamous Cell Carcinoma accounts for nearly 45,000 thousand new cancers per year 
in the United States and in several parts of the world is one of the most frequent cancers. 
Nevertheless, mortality remains at nearly 55% and has not significantly changed since contemporary 
radiation therapy was implemented over thirty years ago. Patients with HNSCC are afflicted with a 
disease process which may have profound effects on speech, swallowing, cosmesis, and frequently 
cause social isolation. Unfortunately, all current treatment modalities, including radiation therapy, 
surgery, and chemotherapy, continue to have limited effectiveness in patients with advanced 
disease. Local/regional control remains a major issue in this patient population with only 
approximately 10% of patients with advanced disease succumbing to distant disease alone. The 
rational development of new therapies for HNSCC will depend on an understanding of the biology of 
this cancer at the molecular l^vel. Molecular analysis has identified critical molecular events leading to 
HNSCC development and progression. The goal of this research is to directly modify the cancer cell to 
express large quantities of exogenously introduced a normal tumor suppressor gene product that 
suppresses the characteristics of the malignant phenotype. 
The purpose of this protocol is to investigate molecular mechanisms that may influence the growth 
and progression of HNSCC; our goal is development of therapeutic agents specifically targeted at the 
molecular level. Approximately 80-85% of head and neck cancers are squamous cell carcinomas. 
Much of the current data on the molecular progression model of HNSCC has shown that multiple 
molecular events occur in the carcinogenic cascade. Although molecular studies have shown p53, 
int-2, Rb, Prad-1 , and c-erb B2/Neu may all be involved in HNSCC, loss of heterozygosity 
microsatellite analysis has shown 3p, 9p, 14q, and 17p are frequent sites of loss (>40%) in adjacent 
premalignant areas. 1 The control and survival rates of patients with advanced head and neck cancers 
are low despite aggressive local regional therapy. Although dramatic responses have been observed 
with chemotherapy, its impact upon survival is minimal. Established biologic predictors of chemo or 
radiation therapy response have remained elusive. HNSCC also may serve as a model for other 
carcinogen-induced malignancies. The approaches and observations developed in this study may be 
applicable to other types of epithelial cancers. 
Abundant evidence has accumulated that the process of malignant transformation is mediated by a 
genetic paradigms. The major lesions detected in cancer cells occur in dominant oncogenes and 
tumor suppressor genes. Dominant oncogenes have alterations in a class of genes called proto- 
oncogenes, which participate in critical normal cell functions, including signal transduction and 
transcription. Primary modifications in the dominant oncogenes that confer the ability to transform 
include point mutations, translocations, rearrangements, and amplification. Tumor suppressor genes 
appear to require homozygous loss of function, by mutation, deletion, or a combination of these for 
transformation to occur. Some tumor suppressor genes appear to play a role in the governance of 
proliferation by regulation of transcription. It is possible that modification of the expression of 
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Recombinant DNA Research, Volume 20 
