SPOREs : Organ-Specific SPORE Programs : Head and Neck

Purpose and Intent: This Head and Neck SPORE Application has developed out of the multidisciplinary translational head and neck cancer research program of the UPCI. This program has transcended departmental and institutional lines to form an integrated multidisciplinary research team dedicated to advancing the detection, treatment and prevention of head and neck cancer. The clinicians and scientists included in this application represent multiple departments and areas of expertise. They have been selected for participation in this SPORE application because of their dedication to translational cancer research and their track record of collaborating effectively to accomplish this objective. Multiple potential projects have been presented and reviewed by the Executive committee, the Internal Scientific Advisory Board and by members of the External Scientific Advisory Board. The comments in the critique of the previous SPORE application also have been reviewed carefully and all of the evaluations and advice have been factored into the decisions leading to the current choice and design of the proposed projects. Many of our investigators have peer-reviewed funding directly related to head and neck cancer. Each project includes both basic and clinical Co-Principal Investigators, in addition to other key co-investigators, in order to develop the synergy necessary in translational research. Thus, the leadership of each project has complementary strengths and areas of expertise that will optimize the translation of new findings to clinical therapies and screening procedures. By integrating laboratory findings with clinical research and epidemiologic data, the results of our studies will rapidly be disseminated to the community of head and neck cancer clinicians and scientists, to optimize the benefits for all patients with this disease.

This SPORE will use the comprehensive care and research facilities and infrastructure of the UPCI, including the Shared Resources supported by its Cancer Center Support Grant from the NCI. In addition to the four projects, the SPORE will have three dedicated core resources: an administrative core, a tissue procurement and pathology core, and a biostatistics core. These cores will provide specialized, individualized support for the SPORE investigators by: 1) overseeing project administration, evaluating career development and developmental research projects and reviewing current and proposed projects; 2) procuring, processing, storing and distributing human tissue specimens; and 3) assisting with data management, providing statistical support for data analysis of molecular epidemiologic studies and clinical trials, and aid in the design of early phase clinical studies to investigate novel therapeutic strategies. To facilitate the development of future research in head and neck cancer, the SPORE will include a Developmental Research Program and a Career Development Program.

Project 1: Cyclin D1 and XPD Polymorphisms as potential risk factors of SCCHN
Co-Project Leader: Marjorie Romkes, PhD
Co-Project Leader: Joel Weissfeld, MD, MPH
Co-Investigator: Jonas T. Johnson, MD
Col-Investigator: Susanne M. Gollin, PhD

Our objective is to address the fundamental question concerning the extent to which genetic background modulates human susceptibility to head and neck squamous cell carcinoma (SCCHN). Interindividual and interethnic differences in tobacco carcinogen metabolism are considered to be major contributors to variations observed in disease susceptibility. In addition to variability in activation and detoxification pathways of mutagenic agents, variability in the capacity to repair smoking induced DNA damage is likely to represent another major family of susceptibility biomarkers. The nucleotide excision repair (NER) system is important in the repair of chemical carcinogen induced genotoxic damage. The XPD protein is a key member of this pathway and mutations in the XPD gene, including the common A35931C (Lys751 Gln) variant allele result in reduced repair capacity. Cyclin D1 (CCND1) is an essential cell cycle regulatory protein and is reported to enhance alternate splicing and increase cyclin D1 protein half-life; consequently subjects with the variant allele may have increased susceptibility to increased cell proliferation and the promotion of genetic instability by the bypass of the G1/S checkpoint of the cell cycle control mechanism.

We propose to asses the effect of genetic polymorphisms in the XPD and CCND1 genes on susceptibility to HNSCC in order to further refine the HNSCC risk assessment model for individuals with smoking and/or alcohol consumption. We plan to extend our initial observations of an association between elevated risk of upper aerodigestive tract cancer among individuals who carried both the CCND1870A variant allele and XPD G1n allele (10.4, 95% CI 5.3-20.4). In specific aim 1, we will validate these results in a series of matched SCCHN cases (N=750) and controls (N=1000). Specific aim 2 will evaluate whether these CCND1 and/or XPD genetic polymorphisms are associated with elevated risk of recurrence or development of a second primary tumor. In specific aim 3, we propose to determine the correlation between CCND1 and XPD polymorphisms in peripheral blood mononuclear cells (PBMC) and, genetic alterations in SCCHN tissues.

Project 2: Therapeutic Inhibition of the Stat3-to-bcl-xl Signaling Axis in SCCHN
Co-Investigator: Jennifer R. Grandis, MD
Co-Investigator: Daniel Johnson, MD
Consultant: Merrill J. Egorin, MD

Signal Transducers and Activators of Transcription (STATs) are intracellular signaling proteins that are activated upon tyrosine phosphorylation and translocate from the cytosol to the nucleus where they bind to specific regions of DNA and exert transcriptional activity. Stat3 activation has been linked to transformation and tumor progression in several cancers, including squamous cell carcinoma of the head and neck (SCCHN). We have accumulated convincing evidence that constitutive Stat3 activation in SCCHN represents a critical survival pathway in SCCHN via activation of the anti-apoptotic protein, BCL-X L. We reported that activated Stat3 stimulated SCCHN growth independent of upstream growth factor receptors including EGFR. Further investigation demonstrated that activated Stat3 could be selectively targeted with a double stranded “decoy” oligodeoxynucleotide (ODN) representing the high affinity serum inducible element (hSIE). Blocking activated Stat3 with a Stat3 decoy inhibited SCCHN proliferation and Stat3-mediated gene expression with no effect on the growth of normal mucosal epithelial cells. Additionally, we have developed a potent pro-apoptotic peptide (Bax BH3 peptide) that binds and inhibits Bcl-X L protein, the downstream mediator of Stat3 anti-apoptotic activity.

Therefore, the overall aim of this proposal is to develop a therapeutic strategy that targets Stat3 signaling, thereby inhibiting SCCHN progression. A transcription factor decoy approach will be used as a primary strategy to achieve maximal anti-tumor effects, and a BH3 domain peptide will be investigated as an inhibitor of the Stat3 target Bcl-X L. The ultimate goal will be the development of a therapeutic strategy for SCCHN patients. To accomplish the goals of this proposal, we will: 1) investigate the impact of BAX BH3 peptide on SCCHN cells; 2) investigate strategies for achieving synergism in the killing of SCCHN cell lines; 3) optimize in vivo anti-tumor effects of Stat3 decoy by combining the decoy with BAX BH3 peptide, cytotoxic chemotherapy, or EGFR inhibition; and 4) determine in the phase I setting, the maximum tolerated dose (MTD) and biologic effects of intratumoral Stat3 decoy therapy in SCCHN patients.

Project 3: Wild Type p53-based Adjuvant Immunotherapy for SCCHN
Co-Leader: Albert B. DeLeo, MD
Co-Leader: Robert L. Ferris, MD, PhD
Co-Investigator: Theresa L. Whiteside, PhD
Co-Investigator: Sanjiv Agarwala, MD

Novel adjuvant therapies for head and neck cancer (HNC) are urgently needed, since the survival from this disease has not improved significantly in over 30 years. Recent advances in the development of antitumor vaccines have created an opportunity for evaluation of such vaccines in patients with SCCHN. In general, many shared human tumor antigens are derived from proteins overexpressed in tumors relative to normal cells. Alteration in the tumor suppressor protein, p53, is one of the most common events in human cancers, but mutant p53-based immunotherapy would require “custom made” vaccines for use in relatively few patients. Since most mutations of p53, however, are associated with accumulation or “overexpression” of mutant p53 in the tumor cytosol, the protein is readily accessible to degradation into peptides for immune recognition. Thus, a vaccine targeting wt p53 peptides derived not from the specific mutations but from normal epitopes in the altered p53 molecules, appears to be a more attractive approach to developing broadly-applicable p53-based cancer vaccines. Based on our preliminary results, we propose a phase I clinical trial of a DC-based multi-epitope wt p53 vaccine that contains two HLA-A*0201 (HLA-A2.1)-restricted T-cell-defined p53 peptides plus either a wt p53 or nonspecific helper peptide. This project also includes extensive ex vivo immunological analyses of the SCCHN patients’ responses to immunization as well as tumor characterization to determine whether the tumor is capable of presenting the targeted wt p53 epitopes. Preclinical work developing another wt p53 T helper peptide, with broader HLA binding will also be performed. Results from the in vitro analyses and immunologic responses to the phase I vaccine trial will be combined to facilitate the continued development of p53-based immunotherapy for SCCHN, enabling the design of a future phase II wt p53-based vaccine trial.

Project 4: Targeting EGFR and GPCR Signaling in SCCHN
Co-Leader: Jennifer R. Grandis, MD
Co-Leader: Jill Siegfried, PhD

Squamous cell carcinoma of the head and neck (SCCHN) is known to develop through complex genetic and epigenetic alterations in genes that control cell proliferation, cell cycle, and cell survival. One set of genes that shows frequently altered expression are genes for growth factors and their receptors, including Epidermal Growth Factor Receptor (EGFR). G-protein-coupled receptors (GPCRs) have been shown to activate the EGFR in SCCHN, resulting in increased proliferation and invasion. This proposal will address the effect on SCCHN cell growth and survival of GPCR signaling cascades that show a dual mechanism: one that is EGFR-independent, as well as one that is integrated with the EGFR. Our preliminary results suggest that two GPCR systems, prostaglandin E2 (PGE2) and its receptors, and bradykinin (BK) and its receptors, stimulate SCCHN proliferation by this dual mechanism. The overall goal of this proposal is to demonstrate the mechanism and importance of signaling through PGE2 and BK in head and neck cancer proliferation, and develop a rationale for combining inhibitors of these GPCR pathways with EGFR inhibitors for the treatment of SCCHN. The long-term goal is to design a clinical trial combining EGFR inhibitors with inhibitors of PGE2 or BK for head and neck cancer patients.

Core A: Administrative Core
Co-Leader: Jennifer R. Grandis, MD
Co-Leader: Eugene N. Myers, MD
Administration: Judy Keller
Administrator: Denise Boozer

The Administrative Core (Core A) will provide oversight of all SPORE activities including the Projects, Cores, Developmental Research Program, and Career Development Program. The Core will ensure compliance with all local, federal and NCI regulations and requirements. The Core will assume responsibility for communication and consultation with NCI personnel in preparation of all required reports and publications. The Core will assume responsibility for all fiscal and budgetary functions. The Core will organize all meetings including the monthly SPORE investigators meeting, meetings with the Executive Committee as well as the Internal and External Scientific Advisory Boards. The Core will establish and monitor policies for the recruitment of women and minorities, both as participants on SPORE trials, and also as SPORE investigators. The Core will coordinate travel of SPORE investigators to the annual NCI-sponsored SPORE meeting as well as to an annual Head and Neck SPORE meeting. The Core will interact with the Developmental Research Program and the Career Development Program to ensure smooth functioning of these SPORE components. The Core will coordinate activities with the University of Pittsburgh Cancer Institute to avoid redundancy and ensure that joint activities between the UPCI Head and Neck Cancer Program and the Head and Neck Cancer SPORE are carried out efficiently and that the programs are complementary and synergistic. The Administrative Core will interact with the NCI Program office to ensure that the SPORE guidelines are followed and that the mandate of the SPORE program is carried out. The Core will also facilitate collaborations with the Lung Cancer SPORE at UCPI and Head and Neck Cancer SPORE programs funded at other institutions.

Core B
Core Leader, Jennifer L. Hunt, MD
E. Leon Barnes, MD
Bobby M. Collins, DDS
Jonas T. Johnson, MD

The University of Pittsburgh Head and Neck Cancer SPORE will establish a Hisology/Tissue Banking Core to ensure efficient use of head and neck tissue specimens and provide routine and specialized histologic evaluation of these tissues for the SPORE's research projects. The goal is to provide sufficient and well characterized tissues of the highest quality in support of research studies in this SPORE and those of collaborating SPORE institutions. Tissue specimens as well as blood and body fluid samples will be systematically collected from head and neck cancer patients or from non-cancer patients to be used as controls. The Core will be responsible for collection, triage, processing and distribution or storage of specimens and tissue histopathology, immunohistochemistry, and interpretation. Research specimens, including snap-frozen, OCT-embedded, archival or fresh tissue blocks, cells (tumor or tumor infiltrating lymphocytes) dissociated from tissues, peripheral blood mononuclear cells, and paraffin embedded or frozen tissue sections for immunohistochemical analysis and tissue microarrays, will be triaged for distribution to the investigators, as specified by the research protocol. Microdissection of tissues and extraction of DNA and/or RNA for molecular assays will also be performed. The Core will bank any samples that are not used immediately by the SPORE investigators for future use by SPORE developmental research projects and SPORE projects at collaborating institutions. Histopathologic analysis by the Core Pathologists will confirm the quality of and the presence of the expected target tissue in research specimens. Immunohistochemistry will be used to detect cellular biomarkers, whose expression in target tissues may be correlated with clinical outcome. The Core will triage samples and facilitate the sharing of specimens by the research laboratories according to a priority schema reviewed and approved by the Executive Committee of the SPORE. Specimen processing, inventory, and distribution data and histopathologic analysis results, will be maintained in the Core's computerized database with links to the Bioinformatics component of the Biostatistics Core for storage and archiving to facilitate a web-based retrieval system. This database will be designed for use by all SPORE investigators.

Core C
Core Leader, Harry S. Wieand, PhD
Co-Leader, John Gilbertson, MD
Biostatistician, William E. Gooding, MS

The immediate primary goal for the Biostatistics Core will be to provide support for the design of studies, the creation of analysis files, the analysis of data, and informatics support of all the projects and cores. A more long-range primary goal is to develop, implement, and maintain a comprehensive research database to support the activities of the Head and Neck Cancer (HNC) Spore. Other goals are to assist with the design of and analyses from pilot studies within the Developmental Research Program, to serve as a resource for the Career Development Program (with direct input into the training of clinical trial development), and to oversee the clinical data management. The Core has statisticians with a track record in methodologic work, considerable experience in the analysis of both laboratory and clinical trial data, has access to outstanding computer facilities, and is in a position to use state of the art statistical software. In addition, members of the Core have played a leadership role in the development of a comprehensive research database across several programs in the cancer center, which will be used as model for the database for the HNC Spore.

Career Development Program Abstract
Co-Director, Theresa L. Whiteside, PhD
Co-Director, Eugene N. Myers, MD

The goal of the Career Development Program in Cancer of the Head and Neck is to recruit and train young or established scientists in the field of the biology as well as clinical and translational research aspects of head and neck cancer (HNC). The Career Development Program is viewed as an essential part of the overall effort of this SPORE to stimulate translational research in HNC. The Career Development Program (CDP) has the following objectives: 1) To recruit physicians, scientists and physician-scientists to the Program who are dedicated to becoming investigators in the field of HNC. 2) To train and guide the recruited candidates through the process of developing into outstanding translational investigators in various areas of HNC biology, including laboratory, clinical and epidemiologic science. The Career Development Program will provide financial support for achieving the goals stated above, while the SPORE itself will provide a nurturing and stimulating mentoring environment for candidates who are being initiated into translational research in this field. The faculty within the SPORE has a long-standing record in mentoring postdoctoral fellows, young scientists and physician-scientists for careers in HNC. The currently funded Research Training Grant in Head and Neck Oncology (T32) will serve as a source of research-oriented candidates to fill the positions available through the Career Development Program. We also plan to support two faculty positions, for a recently recruited physician-scientist and translational scientist during the two initial years of the SPORE. The second recruitment phase for junior faculty will commence in year two of the SPORE. These investigators will be supported in the last two years of the SPORE. The SPORE-initiated recruitment of new faculty will consider candidates identified through the well-defined recruitment process, with special emphases placed on seeking minority candidates and women.

Developmental Research Program Abstract
Co-Leader, William L. Bigbee, PhD
Co-Leader, Susanne M. Gollin, PhD
Co-Leader, Jonas T. Johnson, MD

The Developmental Research Program of the University of Pittsburgh Head and Neck Cancer SPORE will be instituted for the purpose of identifying and facilitating innovative new pilot projects in head and neck cancer research. The overall goal of the Developmental Research Program is to provide seed funding to investigators for novel research in head and neck cancer to further the basic, clinical, and translational research priorities of the Head and Neck Cancer SPORE. Our design for the Developmental Research Program is based on our prior successful experience with other UPCI Pilot Project Programs including the Lung Cancer SPORE Developmental Research Program and the Pilot Project Programs of the Oral Cancer Center at the University of Pittsburgh. Drs. William L. Bigbee, Susanne M. Gollin, and Jonas T. Johnson, with ongoing experience in these related Developmental Research Programs, will provide leadership for translational research. The proposed Developmental Research Program budget will include $150,000 per year in funds from the NCI through this proposal, together with an additional $150,000 per year in matching funds from the Eye and Ear Foundation of Pittsburgh. These activities of the Developmental Research Program will stimulate innovative research toward meeting the translational goals of the Head and Neck Cancer SPORE: reduction in the incidence, morbidity, and mortality from head and neck cancer.

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