Head and neck cancer: meeting summary and research opportunities.
ABSTRACT 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.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is marked by immunosuppression, a state in which the established tumor escapes immune attack. However, the impact of the premalignant and tumor microenvironments on immune reactivity has yet to be elucidated. The purpose of this study was to determine how soluble mediators from cells established from carcinogen-induced oral premalignant lesions and HNSCC modulate immune cell cytokine production. It was found that premalignant cells secrete significantly increased levels of G-CSF, RANTES, MCP-1, and PGE2 compared to HNSCC cells. Splenocytes incubated with premalignant supernatant secreted significantly increased levels of Th1-, Th2-, and Th17-associated cytokines compared to splenocytes incubated with HNSCC supernatant. These studies demonstrate that whereas the premalignant microenvironment elicits proinflammatory cytokine production, the tumor microenvironment is significantly less immune stimulatory and may contribute to immunosuppression in established HNSCC.Cancers. 01/2014; 6(2):756-70.
- [Show abstract] [Hide abstract]
ABSTRACT: To assess the expression of COX-2,CD44v6 and CD147 in hypopharyngeal squamous cell carcinomas and the three biomarkers correlation with tumor invasion and lymph node metastasis of Chinese people. 101 cases of surgically excised primary tumor were included in this study, and 40 tissues of epithelium adjacent to carcinoma were used as controls. We characterized the immunohistochemical expression of COX-2, CD44v6, and CD147 in141 formalin-fixed, paraffin-embedded tissues, and measured the mean optical density (OD) of the positive area to identify the expression of the three bio-markers and relationship with tumor invasion and lymph node metastasis. Our study demonstrates that the expression of the COX-2 and CD147 were significantly increased in carcinoma tissues compared to the epithelium adjacent to carcinoma. We also observed that the expression of COX-2, CD44v6, and CD147 were significantly associated with T classification, lymph node metastasis and clinical stage. There was strong significant correlation among the three biomarkers as well. Additionally, we indicated that recurrence and ≥P50 level of COX-2 expression had an independent prognostic effect on prognosis. In conclusion, the three biomarkers play important roles in tumor invasion and lymph node metastases and might be valuable indicators of tumor metastasis in hypopharyngeal squamous cell carcinoma.PLoS ONE 01/2013; 8(9):e71048. · 3.53 Impact Factor
Article: Towards Neuroimmunotherapy for Cancer: the Neurotransmitters Glutamate, Dopamine and GnRH-II augment substantially the ability of T cells of few Head and Neck cancer patients to perform spontaneous migration, chemotactic migration and migration towards the autologous tumor, and also elevate markedly the expression of CD3zeta and CD3epsilon TCR-associated chains.[Show abstract] [Hide abstract]
ABSTRACT: In previous studies we found that several Neurotransmitters and Neuropeptides among them: Glutamate, Dopamine, Gonadotropin-releasing-hormone (GnRH) I and II, Somatostatin, CGRP and Neuropeptide Y, can each by itself, at low physiological concentration (~10 nM) bind its receptors in human T cells and trigger several key T cell functions. These findings showed that the nervous system, via Neurotransmitters and Neuropeptides, can 'talk' directly to the immune system, and stimulate what we coined 'Nerve-Driven Immunity': immune responses dictated by the nervous system. In various human cancers, the immune system of the patients, and their T cells in particular, are not functioning well enough against the cancer due to several reasons, among them the suppressive effects on the immune system induced by: (1) the cancer itself, (2) the chemotherapy and radiotherapy, (3) the ongoing/chronic stress, anxiety, depression and pain felt by the cancer patients. In Head and Neck Cancer (HNC), 5-year survival rate remains below 50 %, primarily because of local recurrences or second primary tumors. Two-thirds of HNC patients are diagnosed at advanced clinical stage and have significantly poorer prognosis. Most HNC patients have multiple severe immunological defects especially in their T cells. A major defect in T cells of patients with HNC or other types of cancer is low CD3zeta expression that correlates with poor prognosis, decreased proliferation, apoptotic profile, abnormal cytokine secretion and poor abilities of destructing cancer cells. T cells of cancer patients are often also unable to migrate properly towards the tumor. In this study we asked if Glutamate, Dopamine or GnRH-II can augment the spontaneous migration, chemotactic migration and towards autologous HNC migration, and also increase CD3zeta and CD3epsilon expression, of peripheral T cells purified from the blood of five HNC patients. These HNC patients had either primary tumor or recurrence, and have been already treated by surgery and/or radiotherapy and/or chemotherapy without satisfactory outcomes. We found that Glutamate, Dopamine and GnRH-II, each by itself, at 10 nM, and during 30 min incubation only with the peripheral T cells of the HNC patients increased substantially their: (1) spontaneous migration (up to 4.4 fold increase), (2) chemotactic migration towards the key chemokine SDF-1 (up to 2.3 fold increase), (3) migration towards the autologous HNC tumor removed surgically ~48 h earlier in a pre-planned operation (up to 3.5 fold increase). Each of the Neurotransmitters even 'allowed' the T cells of one HNC patient to overcome completely the suppressive anti-migration effect of his autologous tumor, (4) cell surface CD3zeta expression (up to 4.3 fold increase), (5) cell surface CD3epsilon expression (up to 1.9 fold increase). If the absolutely essential larger scale subsequent studies would validate our present findings, Glutamate, Dopamine and GnRH-II could be used for a completely novel indication: adoptive T cell immunotherapy for some patients with HNC and maybe also other types of cancer. We coin here a novel term-'Neuroimmunotherapy' for this new form of T cell immunotherapy, based on the direct activation of the patient's own T cells by Neurotransmitters. Such 'Neuroimmunotherapy' could be reduced to practice by rather simple, painless and repeated/periodical removal of peripheral T cells from the cancer patients, activating them ex vivo for 30 min by either Glutamate, Dopamine or GnRH-II, and infusing them back to the patients by intravenous and/or intratumoral injection. The 'rejuvenated' Neurotransmitter-treated T cells are expected to have significantly improved abilities to reach and eradicate the cancer, and also combat infectious organisms that cancer patients often suffer from. Since the T cells are autologous, since the Neurotransmitters are physiological molecules, and since the ex vivo 'parking period' is very short, such Neuroimmunotherapy is expected to be very safe.Journal of neural transmission (Vienna, Austria : 1996). 07/2014;
2004;64:8126-8129. Cancer Res
Jennifer R. Grandis, Jennifer A. Pietenpol, Joel S. Greenberger, et al.
Head and Neck Cancer : Meeting Summary and Research
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[CANCER RESEARCH 64, 8126–8129, November 1, 2004]
Head and Neck Cancer: Meeting Summary and Research Opportunities
Jennifer R. Grandis,1Jennifer A. Pietenpol,3Joel S. Greenberger,2Richard A. Pelroy,4and Suresh Mohla4
University, Nashville, Tennessee; and4Division of Cancer Biology, National Cancer Institute, Bethesda, Maryland
1Otolaryngology and Pharmacology and
2Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania;
3Department of Biochemistry, Vanderbilt
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 un-
derstanding 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 under-
studied 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 communi-
cate these research goals to the cancer biology community and encourage
more interest in HNSCC as a tumor model to test translational research
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 (Uni-
versity of Texas M. D. Anderson Cancer Center, Houston, TX) sum-
marized 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
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 qual-
ity of life and functional outcomes as primary end points.
R. Weichselbaum (University of Chicago, Chicago, IL) discussed
radiation therapy advancements in defining optimal fractionation reg-
imens 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 pro-
tection of normal tissues are another approach (3).
The molecular alterations that characterize HNSCC were addressed
in the second session. D. Sidransky (Johns Hopkins University, Bal-
timore, 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
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 oppor-
tunity 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 par-
adigms 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, impli-
cating 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 (Univer-
sity 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 associ-
ated with failure of laryngeal preservation in this trial, providing the
rationale for Bcl-xLas a therapeutic target in HNSCC (8). Gossypol,
a naturally occurring polyphenolic yellow pigment present in cotton-
seed products, was discovered via small molecule screens to bind to
Bcl-xLand the levorotatory isomer and is now in development for
Received 7/8/04; accepted 9/1/04.
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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,
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©2004 American Association for Cancer Research.
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clinical application as an inducer of apoptosis in cisplatin-resistant
Invasion of local and regional tissues is responsible for tremendous
morbidity and mortality in HNSCC. R. Kramer (University of Cali-
fornia San Francisco, San Francisco, CA) presented a model of
stepwise invasion in which epithelial cells dissociate from neighbor-
ing cells, elaborate proteases, and motility factors and initiate down-
stream signaling through integrin receptors to activate the cytoskele-
ton 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 pre-
malignant lesions. Human papilloma virus (HPV) infection is emerg-
ing 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 plat-
forms, 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 data-
base.6Use 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 assess-
ment 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 acces-
sibility 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 process-
ing techniques including developing standard operating procedures
(SOPs) for serum to facilitate proteomic studies. M. Becich (Univer-
sity 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 bio-
informatics 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 pep-
tides 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 Washing-
ton, 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 ? 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 (?5?1, ?5?3, and ?4?1) exert their
angiogenic effects by regulating key cells including endothelial
cells, pericytes, circulating progenitor cells, monocytes, and stro-
mal 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 summa-
rized 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
HEAD AND NECK CANCER
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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 pro-
spective 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 Oncol-
ogy Group study to date is an ongoing trial of lymphatic mapping and
sentinel node lymphadenectomy for patients with T1N0or T2N0oral
squamous cell carcinoma. He emphasized the need to collect speci-
mens 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 com-
bined 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
Conclusions of the Workshop
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
The overall consensus was that HNSCC represents an important
tumor model that is eminently ripe for intensive investigation. Com-
pared 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 fraction-
ation; 2) multidisciplinary management as demonstrated by the in-
creasing 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) appreci-
ation of the role of the immune system in HNSCC development and
Table 1 HNSCC research issues, barriers, and solutions identified by The Head and Neck Cancer: Research and Therapeutic Opportunities Workshop
Issues, barriers, and solutions
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.
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.
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.
HEAD AND NECK CANCER
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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 intra-
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 scien-
tists and clinicians at individual institutions should be encouraged. It
is recommended that these collaborations focus on addressing the
1. Development of methods to reproducibly measure the expres-
sion 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
2. Characterization of the molecular signatures of precursor le-
sions, established tumors, and metastatic disease to aid in de-
signing therapeutic interventions.
3. Definition and integration of genomic, transcriptional, and pro-
teomic 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
4. Validation of relative prognostic predictive values of various
biomarkers using specimens of well-characterized patients en-
rolled 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 hy-
poxia-induced resistance of HNSCC to ionizing radiation or
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
9. Initiation of clinical trials using molecular targeting agents that
emphasize tissue collection and analysis to validate new molec-
ular 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 pharmaceuti-
cal and biotechnology entities.
The explosion of information that has resulted in improved preven-
tion, diagnosis, and treatment of cancer has not traditionally been
applied to HNSCC. Specific issues and barriers to the clinical appli-
cation 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 Work-
shop 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 Clay-
man, 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 Weichsel-
baum, Theresa Whiteside, Gregory Wolf, Albert Wong, Tzyy-Choou Wu, and
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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.
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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:
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:
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 chemo-
therapy and organ preservation. Laryngoscope 2002;112:638–44.
9. Zhang K, Kramer RH. Laminin 5 deposition promotes keratinocyte motility. Exp Cell
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
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, biojec-
tor, 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:
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 radiore-
sistance 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
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:
HEAD AND NECK CANCER
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