Head and neck squamous cell carcinoma (HNSCC) is the most common malignant neoplasm arising in the mucosa of the upper aerodigestive tract. Nearly two thirds of patients present with advanced (stage III and IV) disease. Fifty percent of HNSCC patients die of their disease, and 5% of HNSCC patients per year will develop additional second primary tumors. Currently used therapeutic modalities (surgery, radiation, and/or chemotherapy) have been associated with rather modest improvements in patient survival. The Head and Neck Cancer: Research and Therapeutic Opportunities Workshop (held in Washington, DC, May 24–26, 2004) was organized by the Division of Cancer Biology at the National Cancer Institute to identify research areas and directions that will advance understanding of HNSCC biology and accelerate clinical translation. The primary goal of the workshop was to identify the barriers that impede basic science discovery and the translation of these developments to the clinical setting. Over a 2.5-day period, experts in both HNSCC and other cancer-related fields met to identify and prioritize the key areas for future research. The overall consensus was that HNSCC is a relatively understudied malignancy and that investigations that focus on the biology of this tumor have the potential to impact significantly on the prevention and treatment of epithelial malignancies. The chief objective is to communicate these research goals to the cancer biology community and encourage more interest in HNSCC as a tumor model to test translational research hypotheses.

Three overview talks set the stage of the introductory session by summarizing the current status of medical oncology, surgery, and radiation oncology approaches for head and neck squamous cell carcinoma (HNSCC) prevention and management. W. K. Hong (University of Texas M. D. Anderson Cancer Center, Houston, TX) summarized his 30-year experience by highlighting the multistep oral carcinogenesis progression model and discussed the major clinical studies that have emerged from his translational research program. Given the cumulative negative results of the single-agent retinoid prevention trials, an emphasis was placed on biochemoprevention using multiple agents that target several pathways and on the complete characterization of individual lesions so that they can optimally be treated (1).

G. Wolf (University of Michigan, Ann Arbor, MI) acknowledged that there had been significant advancements in surgery for HNSCC over the past few decades; however, these have not translated into significant improvements in survival. The failure of these discoveries to result in improved patient survival is due to the heterogeneous nature of HNSCC, the significant comorbidities present in the patient population, a high rate of synchronous and metachronous primary tumors, and the significant immune impairment of HNSCC patients. Surgical innovations have included microvascular reconstructions, endoscopic laser resection, and conservation laryngeal surgery. With combined modality treatment using both chemotherapy and radiation playing an increasingly important role as an alternative to primary surgery, improved surveillance is required with an emphasis on quality of life and functional outcomes as primary end points.

R. Weichselbaum (University of Chicago, Chicago, IL) discussed radiation therapy advancements in defining optimal fractionation regimens and focused dose delivery with the goal of sparing normal tissue. He focused on transcriptional targeting of a radioinducible/chemoinducible gene therapy strategy and enhancing oncolytic viral gene therapy. By combining viral gene therapy with radiation therapy, preliminary results suggest that cellular stress kinases induced by radiation “power-up” the virus by enhancing viral replication (2). In addition, strategies using MnSOD-plasmid gene therapy for the protection of normal tissues are another approach (3).

The molecular alterations that characterize HNSCC were addressed in the second session. D. Sidransky (Johns Hopkins University, Baltimore, MD) summarized the early detection and risk models of HNSCC with an emphasis on preneoplastic lesions as the ideal targets for therapeutic/preventive intervention. Studies analyzing the genetic and epigenetic changes in premalignant lesions as well as invasive cancers have allowed the identification of those alterations that can predict progression to more advanced disease (4). He noted that 46% of HNSCC tumors demonstrate mutations in mitochondrial DNA and that the clinical application of this finding will be facilitated by the imminent availability of a mitochondrial DNA chip for hybridization (5).

C. Arteaga (Vanderbilt University, Nashville, TN) emphasized the need for new models to verify targets and therapeutic efficacy of molecular targeting agents. Interval assessment of cellular activity of the target in the tumor tissue in breast cancer has provided an opportunity to predict clinical utility and subsequently prioritize the use of targeting agents (6). He strongly encouraged the HNSCC community to consider a new paradigm: delivery of an experimental therapy for a short term (e.g., 2 weeks) followed by surgery and analysis of the tissue to assess response. The application of signal transduction paradigms to cancer progression models was presented by M. Weber (University of Virginia, Charlottesville, VA). Studies have shown that cancer cells expressing kinase-dead epidermal growth factor receptor (EGFR) still signal through mitogen-activated protein kinase, implicating EGFR as a platform for integration of intracellular signaling pathways (7). Given the widespread expression of EGFR in HNSCC and the wealth of information from clinical trials to date using EGFR targeting agents, this area is ripe for investigation. T. Carey (University of Michigan, Ann Arbor, MI) discussed the VA larynx trial as a paradigm for prospective specimen collection to determine markers of response. Expression of Bcl-xL, an antiapoptotic protein, was associated with failure of laryngeal preservation in this trial, providing the rationale for Bcl-xL as a therapeutic target in HNSCC (8). Gossypol, a naturally occurring polyphenolic yellow pigment present in cottonseed products, was discovered via small molecule screens to bind to Bcl-xL and the levorotatory isomer and is now in development for clinical application as an inducer of apoptosis in cisplatin-resistant HNSCC.

Invasion of local and regional tissues is responsible for tremendous morbidity and mortality in HNSCC. R. Kramer (University of California San Francisco, San Francisco, CA) presented a model of stepwise invasion in which epithelial cells dissociate from neighboring cells, elaborate proteases, and motility factors and initiate downstream signaling through integrin receptors to activate the cytoskeleton and trigger cell locomotion. Cumulative evidence suggests that laminin 5 is a key stimulus for HNSCC migration and may represent a robust therapeutic target (9). G. Clayman (University of Texas M. D. Anderson Cancer Center, Houston, TX) summarized the development of adenoviral p53 gene therapy for HNSCC treatment and prevention. Prior studies have demonstrated therapeutic efficacy in preclinical models and a good safety profile with intratumoral administration in early-phase clinical studies (10). Two phase III clinical trials are under way in addition to topical and intralesional approaches for oral premalignant lesions. Human papilloma virus (HPV) infection is emerging as a potential risk factor and vaccine target for HNSCC. N. Kiviat (University of Washington, Seattle, WA) reported that 20% to 25% of all HNSCC (and 40% of tonsillar HNSCC) are associated with HPV (11). She emphasized the need for more rigorous methods to ascertain HPV infection because the simple presence of HPV DNA does not implicate active or prior infection. The proportion of HPV-positive precursor lesions in HNSCC needs to be defined in light of the early encouraging results of HPV vaccines in cervical cancer prevention. T. C. Wu (Johns Hopkins University, Baltimore, MD) presented an analysis of cellular immune responses against HPV in HNSCC (12). These data provide the rationale for a planned phase I clinical trial to study the safety and immunogenicity of repeated vaccination in HPV-positive HNSCC patients.

The third session focused on applications of advanced technology and bioinformatics. W. Yarbrough (Vanderbilt University, Nashville, TN) presented the promise and pitfalls of proteomics for application in HNSCC. Proteomics can be used to identify protein markers of early disease in surrogate specimens (such as serum and saliva) as well as new biomarkers from primary tumors to predict clinical behavior. Limitations include a limited mass range and difficulty in identification of proteins for some commonly used proteomic platforms, as well as the inability to correlate relative levels of proteins between multiple samples. E. Petricoin (United States Food and Drug Administration, Rockville, MD) presented the concept of molecular profiling to individualize patient care. He presented recent discoveries suggesting that biomarkers of importance may be bound to more highly abundant serum proteins (e.g., albumin). New strategies are in place to enrich serum samples for these key proteins. In addition, phosphoproteomics is being developed as a way to interrogate select signaling pathways in tissues. To date, his group has validated over 300 phospho-specific antibodies for use on a protein chip platform.5 HNSCC specimens from patients treated with agents that target signal transduction pathways can be assessed using this approach.

Gene discovery in HNSCC was discussed by S. Gutkind (National Institute of Dental and Craniofacial Research, Bethesda, MD), who highlighted the Head and Neck-Cancer Genome Anatomy Project, which began in 1998 as a collaborative effort to create a complete database of genes (both novel and known) expressed in HNSCC cell lines and tumors. To date, libraries have been created from >600 tumors, and >150,000 sequences have been entered into the database.6 Use of this database can aid in elucidating the function of novel and known genes in HNSCC. S. Ramaswamy (Harvard University, Cambridge, MA) presented a new model for studying metastasis. In contrast to prior stochastic views, this model is based on the assessment of gene expression profiles in primary tumors and metastases, which suggests that the propensity to metastasis can be determined by the gene profile of the primary tumor (13). Given the relative accessibility of primary HNSCC tumor and paired metastases from cervical lymph nodes, additional gene expression studies using these tissues should be informative. Bioinformatics is essential for collecting and analyzing clinical and laboratory data, especially in this era of Health Information Portability Accountability Act regulations. There is a tremendous need for standardization of tissue collection and processing techniques including developing standard operating procedures (SOPs) for serum to facilitate proteomic studies. M. Becich (University of Pittsburgh, Pittsburgh, PA) emphasized the role of the National Cancer Institute (NCI) in developing SOPs and the importance of the tissue bank and pathology tools workspace on the NCI cancer bioinformatics grid (CaBIG).

The obstacles present in imaging and targeting the tumor tissue were the topic of the fourth session. D. Hallahan (Vanderbilt University, Nashville, TN) presented the use of radiation-inducible neoantigens as a mechanism to deliver drugs to HNSCC tumors. Using phage-display methodology, his group has identified peptides that selectively bind to irradiated tumors (14). These peptides can be conjugated to drug containing liposomes (e.g., cisplatin), thereby providing a new model to target delivery of cytotoxins or radiation to the tumor while sparing nontumor tissue and reducing systemic toxicity. Functional and molecular imaging for cancer applications was discussed by K. Krohn (University of Washington, Seattle, WA), who emphasized that biological processes at the cellular and molecular level can be characterized using remote imaging detectors. Technology requires the availability of probe molecules that can be detected by imaging. Whereas 2-[18F]fluoro-2-deoxy-d-glucose (FDG) has been studied as an imaging tool in HNSCC (15), he emphasized the need to go beyond FDG to incorporate new probes that can theoretically image proliferating cells [e.g., the thymidine analog 3-deoxy-3[18F]fluorothymidine (FLT)] or apoptotic cells (e.g., annexin 5; ref. 16). C. Chao (University of Texas M. D. Anderson Cancer Center, Houston, TX) discussed targeting hypoxic tumor cells with radiotherapy. The development of intensity-modulated radiation therapy (IMRT) allows for dose painting with high precision to spare normal tissue and target tumor cells. However, even with IMRT, there is a 25% to 40% local failure rate within the high-dose region of treatment. He discussed potential strategies to address this problem including use of hypoxia-specific chemotherapy (e.g., tirapazamine) and blockade of hypoxia inducible factor-1 α in conjunction with cytotoxic therapy (17). The tumor vasculature has emerged as a critical component for the delivery of therapeutic reagents. The importance of key integrins in the process of tumor angiogenesis was discussed by J. Varner (University of California San Diego, San Diego, CA). These integrins (α5β1, α5β3, and α4β1) exert their angiogenic effects by regulating key cells including endothelial cells, pericytes, circulating progenitor cells, monocytes, and stromal cells (18). She emphasized the exciting prospects for the clinical use of integrin antagonists (generally antibodies) to block angiogenesis and tumor development/progression.

Finally, the status of clinical research was the focus of the fifth session. A. Forastiere (Johns Hopkins University, Baltimore, MD) presented the progress of the HNSCC studies conducted under the auspices of the Eastern Cooperative Oncology Group. She summarized the status of ongoing trials and noted the importance of planning for correlative biomarker studies at the time of trial design so that tissues can be optimally collected and stored for future analyses. The status of the HNSCC trials in the Radiation Therapy Oncology Group was presented by K. Ang (University of Texas M. D. Anderson Cancer Center, Houston, TX), who emphasized the benefit of prospective tissue collection in conjunction with clinical and pathological information on patients treated on these trials. Such collection efforts allowed the Radiation Therapy Oncology Group to demonstrate that EGFR expression is a negative prognostic indicator and a robust predictor for radiation response for HNSCC. J. Myers (University of Texas M. D. Anderson Cancer Center, Houston, TX) presented the more recently established American College of Surgeons Oncology Group, which focuses on the development of clinical trials to address surgical questions. The major American College of Surgeons Oncology Group study to date is an ongoing trial of lymphatic mapping and sentinel node lymphadenectomy for patients with T1N0 or T2N0 oral squamous cell carcinoma. He emphasized the need to collect specimens for correlative studies to facilitate the design of the subsequent studies. An alternative chemoradiotherapeutic approach for advanced HNSCC was presented by M. Posner (Dana Farber Cancer Institute, Boston, MA), who suggested sequential therapy as a model. This treatment regimen includes induction chemotherapy followed by combined chemoradiotherapy followed by surgery if there is residual disease. Recent evidence supports improved efficacy for a three-drug (versus two-drug) combination (19). He noted that the toxicity of such an approach requires intensive support and rehabilitation of the patient.

The conclusions of the workshop were framed in the context of issues, barriers, and solutions to the rather insignificant progress in head and neck cancer translational research. A summary of the most pertinent points raised during the discussion periods is provided in Table 1.

The overall consensus was that HNSCC represents an important tumor model that is eminently ripe for intensive investigation. Compared with other epithelial malignancies (such as breast, lung, and prostate cancer), there have been relatively few important advances, and none of these have translated into improved patient survival. It was generally agreed that the major accomplishments in the field of HNSCC during the past decade include the following: 1) improved delivery of radiation therapy including IMRT and altered fractionation; 2) multidisciplinary management as demonstrated by the increasing use of combined chemoradiotherapy as a primary treatment approach; 3) recognition of the importance of biomarkers as a means to identify therapeutic targets and response to treatment; 4) appreciation of the role of the immune system in HNSCC development and progression with the identification of potential tumor antigens and vaccine strategies as well as the potential importance of HPV in various stages of tumorigenesis; and 5) standard use of FDG/positron emission tomography imaging with an appreciation of the importance of developing more robust noninvasive strategies to image tumor function. It was agreed that more intensive investigation of HNSCC biology could be rapidly translated into clinical benefit given the relatively unique accessibility of these lesions for biopsies and intratumoral administration.

Information about the basic biology of HNSCC must be enhanced. Tangible advances are likely to be accelerated by a more focused and cohesive effort encompassing multiple approaches. Interdisciplinary collaborations among different institutions and between basic scientists and clinicians at individual institutions should be encouraged. It is recommended that these collaborations focus on addressing the following needs:

  1. Development of methods to reproducibly measure the expression profile of biomarkers in HNSCC and normal tissues as well as in surrogate material such as blood and saliva. This includes a comprehensive approach to identify patterns as well as a detailed analysis of the cell type expressing the gene/protein of interest.

  2. Characterization of the molecular signatures of precursor lesions, established tumors, and metastatic disease to aid in designing therapeutic interventions.

  3. Definition and integration of genomic, transcriptional, and proteomic profiling information of HNSCC lesions at various stages of development and progression to provide a comprehensive view of the molecular pathways and networks involved in HNSCC carcinogenesis.

  4. Validation of relative prognostic predictive values of various biomarkers using specimens of well-characterized patients enrolled into large clinical trials who received well-defined therapy and had follow-up data.

  5. Definition of interactions between tumor cells and host stromal cells and the role of inflammatory cells in the development and progression of HNSCC.

  6. Encouragement of molecular and translational studies on hypoxia-induced resistance of HNSCC to ionizing radiation or chemotherapeutic agents.

  7. Development of new in vivo imaging approaches for tumor cell activity and tumor characteristics that predict a poor response to treatment (e.g., hypoxia and angiogenesis).

  8. Creation of guidelines and SOPs for serum, saliva, blood, and tissue collection, so that results obtained at different institutions and placed into workspaces such as CaBIG can be directly compared.

  9. Initiation of clinical trials using molecular targeting agents that emphasize tissue collection and analysis to validate new molecular targets and predict the efficacy of a given therapy.

These goals can be addressed through collaborative efforts with existing structures such as NCI-supported multidisciplinary programs and through continued and enhanced partnerships with pharmaceutical and biotechnology entities.

The explosion of information that has resulted in improved prevention, diagnosis, and treatment of cancer has not traditionally been applied to HNSCC. Specific issues and barriers to the clinical application of tumor biology have been explored, and potential solutions to the hurdles are proposed. There are clear opportunities to change the morbidity and mortality of this cancer. The complex biology of HNSCC and the substantial barriers to clinical translation require that future efforts enlist the participation of investigators with diverse yet complementary perspectives and expertise.

The Head and Neck Cancer: Research and Therapeutic Opportunities Workshop was sponsored by the Division of Cancer Biology, NCI and held at the Holiday Inn (Georgetown, Washington, DC), May 24–26, 2004. In attendance were Joanna Albala, K. Kian Ang, Carlos Arteaga, Michael Becich, Carol Bradford, Thomas Carey, Christine Chung, K. S. Clifford Chao, Gary Clayman, Susan Crawford, Janet Dancey, Robert L. Ferris, Arlene Forastiere, Maura Gillison, Bonnie Glisson, Jennifer R. Grandis, Joel Greenberger, J. Silvio Gutkind, Dennis Hallahan, John Hay, Dwight Heron, Phil Hinds, Wuan Ki Hong, Tim Hui-Ming Huang, Howard Kaufman, Merrill Kies, Nancy Kiviat, Randall Kramer, Kenneth Krohn, Stephen Lai, Suresh Mohla, Jeffrey Myers, Vassiliki Papadimitrakopoulou, Richard Pelroy, Emmanuel Pettricoin, David Pfister, Jennifer Pietenpol, Peter Polverini, Marshall Posner, Sridhar Ramaswamy, John Ridge, James Rocco, Duane Sewell, Dong Shin, David Sidransky, Dinah Singer, Yasaman Shirazi, David Smith, John Sogn, Carter Van Waes, Judith Varner, Everett Vokes, Michael Weber, Ralph Weichselbaum, Theresa Whiteside, Gregory Wolf, Albert Wong, Tzyy-Choou Wu, and Wendell Yarbrough.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Jennifer R. Grandis, Department of Otolaryngology, Suite 500, Eye and Ear Institute Building, 200 Lothrop Street, Pittsburgh, PA 15213.

5

www.clinicalproteomics.steem.com.

6

www.ncbi.nlm.nih.gov/ncicgap/.

Table 1

HNSCC research issues, barriers, and solutions identified by The Head and Neck Cancer: Research and Therapeutic Opportunities Workshop

Issues, barriers, and solutions
Issues 
 Survival for patients with HNSCC has not improved in the past 30 years. 
 Few HNSCC animal models are available. 
 There are an inadequate number of researchers with HNSCC-focused laboratories. 
 There is a need for better three-dimensional in vitro and in vivo models to study the genetic changes and selective forces that contribute to HNSCC progression. 
 Little is known about the molecular and genetic mechanisms that define HNSCC resistance to therapeutic ionizing radiation and chemotherapy. 
 More information is required regarding the role of host cells (inflammatory cells, vascular cells, and stromal fibroblasts) during the transition from premalignant to malignant cells and during HNSCC progression and metastasis. 
 There is a paucity of randomized, prospective trials comparing standard therapies and/or novel therapies with standard treatment. 
 Tissue-specific genomic and proteomic profiles not well understood. 
 The morbidity of organ resection as well as organ preservation (chemoradiation) necessitates the study of organ function and QOL in the context of therapeutic studies. 
 EGFR-targeted treatments are less effective in clinical trials than predicted by preclinical studies. 
 Functional and molecular imaging approaches are not standard for HNSCC management. 
 There is a paucity of molecular targeting strategies available for therapeutic application. 
 HNSCC is an ideal model for primary and secondary prevention efforts. 
 There is a need to study and focus treatment/prevention efforts on premalignant lesions. 
 It is important to determine the viral etiology of HNSCC. 
 There is a need to understand angiogenesis mechanisms and therapeutic strategies. 
 HNSCC is heterogeneous and clinical behavior is often not predicted by standard TNM staging and tumor grade. 
Barriers 
 There is a lack of reproducible and validated animal models that predict clinical response due to challenge and cost of transgenics/knockouts. 
 Limited funding sources have been dedicated for HNSCC research. 
 The identification of individual genes and proteins is costly and difficult. 
 The lack of uniform methods to measure organ function and QOL issues are rarely considered as clinical trial end points. 
 Few studies have collected tissue to determine which patients would be most likely to benefit from EGFR inhibition. 
 Technical and economic hurdles exist for the development of in vivo imaging strategies. 
 Agents to be considered for long-term administration must be safe with minimal toxicity. 
 Most patients with HNSCC present with advanced disease, and premalignant lesions are rarely seen in the academic medical center. 
 Sexual history is not a typical component of HNSCC evaluation, and viral etiologies are underappreciated. 
 It is difficult to establish HNSCC-derived endothelial cells using in vitro and in vivo models of angiogenesis/lymphangiogenesis. 
 Molecular markers of tumor progression and resistance to therapy are not well understood. 
 The barriers to clinical research include regulatory hurdles, HIPAA requirements, and lack of funding to encourage clinical and basic science collaborations. 
Solutions 
 Develop in vitro three-dimensional models and in vivo organotypic and genetic animal model systems that more faithfully recapitulate human disease. These models should help define the molecular lesions and genetic changes during the transition from the premalignant to malignant phenotype and during progression and metastasis. 
 Use profiling approaches to define the expression and activity of the genome and proteome in HNSCC at various stages, corresponding normal tissue, and stroma. 
 Define the role of tumor–host interactions during various stages of HNSCC progression and metastasis. 
 Include biomarker assessment in all clinical trials and consider preoperative molecular targeting to assess biologic efficacy in the target tissue. 
 Build on developments in molecular and optical imaging to devise methods to noninvasively image tumor activity in vivo
 Develop rational strategies for the testing of combination therapies and incorporate organ function and QOL determinations into all clinical studies. 
 Encourage academic and industrial partnerships and monitor surrogate biomarkers to test efficacy of prevention regimens. 
 Initiate collaborations with community physicians and dentists to identify premalignant lesions for prevention and treatment. 
 Study the role of HPV and other viruses in HNSCC development and implement vaccine prevention and treatment trials. 
 Develop HNSCC models of angiogenesis/lymphangiogenesis and encourage clinical trials of angiogenic inhibitors. 
 Incorporate array strategies to molecularly classify HNSCC tumors to identify more aggressive subtypes and develop widely available tumor bank repositories linked with de-identified patient outcome information. 
 Use well-designed phase II trials to guide decisions in design of phase III trials and provide incentives to encourage interinstitutional collaborations. 
Issues, barriers, and solutions
Issues 
 Survival for patients with HNSCC has not improved in the past 30 years. 
 Few HNSCC animal models are available. 
 There are an inadequate number of researchers with HNSCC-focused laboratories. 
 There is a need for better three-dimensional in vitro and in vivo models to study the genetic changes and selective forces that contribute to HNSCC progression. 
 Little is known about the molecular and genetic mechanisms that define HNSCC resistance to therapeutic ionizing radiation and chemotherapy. 
 More information is required regarding the role of host cells (inflammatory cells, vascular cells, and stromal fibroblasts) during the transition from premalignant to malignant cells and during HNSCC progression and metastasis. 
 There is a paucity of randomized, prospective trials comparing standard therapies and/or novel therapies with standard treatment. 
 Tissue-specific genomic and proteomic profiles not well understood. 
 The morbidity of organ resection as well as organ preservation (chemoradiation) necessitates the study of organ function and QOL in the context of therapeutic studies. 
 EGFR-targeted treatments are less effective in clinical trials than predicted by preclinical studies. 
 Functional and molecular imaging approaches are not standard for HNSCC management. 
 There is a paucity of molecular targeting strategies available for therapeutic application. 
 HNSCC is an ideal model for primary and secondary prevention efforts. 
 There is a need to study and focus treatment/prevention efforts on premalignant lesions. 
 It is important to determine the viral etiology of HNSCC. 
 There is a need to understand angiogenesis mechanisms and therapeutic strategies. 
 HNSCC is heterogeneous and clinical behavior is often not predicted by standard TNM staging and tumor grade. 
Barriers 
 There is a lack of reproducible and validated animal models that predict clinical response due to challenge and cost of transgenics/knockouts. 
 Limited funding sources have been dedicated for HNSCC research. 
 The identification of individual genes and proteins is costly and difficult. 
 The lack of uniform methods to measure organ function and QOL issues are rarely considered as clinical trial end points. 
 Few studies have collected tissue to determine which patients would be most likely to benefit from EGFR inhibition. 
 Technical and economic hurdles exist for the development of in vivo imaging strategies. 
 Agents to be considered for long-term administration must be safe with minimal toxicity. 
 Most patients with HNSCC present with advanced disease, and premalignant lesions are rarely seen in the academic medical center. 
 Sexual history is not a typical component of HNSCC evaluation, and viral etiologies are underappreciated. 
 It is difficult to establish HNSCC-derived endothelial cells using in vitro and in vivo models of angiogenesis/lymphangiogenesis. 
 Molecular markers of tumor progression and resistance to therapy are not well understood. 
 The barriers to clinical research include regulatory hurdles, HIPAA requirements, and lack of funding to encourage clinical and basic science collaborations. 
Solutions 
 Develop in vitro three-dimensional models and in vivo organotypic and genetic animal model systems that more faithfully recapitulate human disease. These models should help define the molecular lesions and genetic changes during the transition from the premalignant to malignant phenotype and during progression and metastasis. 
 Use profiling approaches to define the expression and activity of the genome and proteome in HNSCC at various stages, corresponding normal tissue, and stroma. 
 Define the role of tumor–host interactions during various stages of HNSCC progression and metastasis. 
 Include biomarker assessment in all clinical trials and consider preoperative molecular targeting to assess biologic efficacy in the target tissue. 
 Build on developments in molecular and optical imaging to devise methods to noninvasively image tumor activity in vivo
 Develop rational strategies for the testing of combination therapies and incorporate organ function and QOL determinations into all clinical studies. 
 Encourage academic and industrial partnerships and monitor surrogate biomarkers to test efficacy of prevention regimens. 
 Initiate collaborations with community physicians and dentists to identify premalignant lesions for prevention and treatment. 
 Study the role of HPV and other viruses in HNSCC development and implement vaccine prevention and treatment trials. 
 Develop HNSCC models of angiogenesis/lymphangiogenesis and encourage clinical trials of angiogenic inhibitors. 
 Incorporate array strategies to molecularly classify HNSCC tumors to identify more aggressive subtypes and develop widely available tumor bank repositories linked with de-identified patient outcome information. 
 Use well-designed phase II trials to guide decisions in design of phase III trials and provide incentives to encourage interinstitutional collaborations. 

Abbreviations: QOL, quality of life; TNM, tumor-node-metastasis; HIPAA, Health Information Portability Accountability Act.

1
Papadimitrakopoulou VA, Clayman GL, Shin DM, et al Biochemoprevention for dysplastic lesions of the upper aerodigestive tract.
Arch Otolaryngol Head Neck Surg
1999
;
125
:
1083
-9.
2
Weichselbaum RR, Kufe DW, Hellman S, et al Radiation-induced tumour necrosis factor-alpha expression: clinical application of transcriptional and physical targeting of gene therapy.
Lancet Oncol
2002
;
3
:
665
-71.
3
Guo H, Seixas-Silva JA, Jr, Epperly MW, et al Prevention of radiation-induced oral cavity mucositis by plasmid/liposome delivery of the human manganese superoxide dismutase (SOD2) transgene.
Radiat Res
2003
;
159
:
361
-70.
4
Califano J, Leong PL, Koch WM, et al Second esophageal tumors in patients with head and neck squamous cell carcinoma: an assessment of clonal relationships.
Clin Cancer Res
1999
;
5
:
1862
-7.
5
Maitra A, Cohen Y, Gillespie SE, et al The Human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detection.
Genome Res
2004
;
14
:
812
-9.
6
Arteaga CL, Baselga J Tyrosine kinase inhibitors. Why does the current process of clinical development not apply to them?.
Cancer Cell
2004
;
5
:
525
-31.
7
Kulik G, Klippel A, Weber MJ Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt.
Mol Cell Biol
1997
;
17
:
1595
-606.
8
Trask DK, Wolf GT, Bradford CR, et al Expression of Bcl-2 family proteins in advanced laryngeal squamous cell carcinoma: correlation with response to chemotherapy and organ preservation.
Laryngoscope
2002
;
112
:
638
-44.
9
Zhang K, Kramer RH Laminin 5 deposition promotes keratinocyte motility.
Exp Cell Res
1996
;
227
:
309
-22.
10
Clayman GL The current status of gene therapy.
Semin Oncol
2000
;
27
:
39
-43.
11
Gillison ML, Koch WM, Capone RB, et al Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.
J Natl Cancer Inst (Bethesda)
2000
;
92
:
709
-20.
12
Trimble C, Lin CT, Hung CF, et al Comparison of the CD8+ T cell responses and antitumor effects generated by DNA vaccine administered through gene gun, biojector, and syringe.
Vaccine
2003
;
21
:
4036
-42.
13
Ramaswamy S, Ross KN, Lander ES, Golub TR A molecular signature of metastasis in primary solid tumors.
Nat Genet
2003
;
33
:
49
-54.
14
Hallahan D, Geng L, Qu S, et al Integrin-mediated targeting of drug delivery to irradiated tumor blood vessels.
Cancer Cell
2003
;
3
:
63
-74.
15
Fogarty GB, Peters LJ, Stewart J, et al The usefulness of fluorine 18-labelled deoxyglucose positron emission tomography in the investigation of patients with cervical lymphadenopathy from an unknown primary tumor.
Head Neck
2003
;
25
:
138
-45.
16
Schwartz JL, Tamura Y, Jordan R, Grierson JR, Krohn KA Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs.
J Nucl Med
2003
;
44
:
2027
-32.
17
Cowen RL, Williams KJ, Chinje EC, et al Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: reversing tumor radioresistance and effecting cure.
Cancer Res
2004
;
64
:
1396
-402.
18
Jin H, Varner J Integrins: roles in cancer development and as treatment targets.
Br J Cancer
2004
;
90
:
561
-5.
19
Pignon JP, Syz N, Posner M, et al Adjusting for patient selection suggests the addition of docetaxel to 5-fluorouracil-cisplatin induction therapy may offer survival benefit in squamous cell cancer of the head and neck.
Anticancer Drugs
2004
;
15
:
331
-40.