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The University of Texas M. D. Anderson Cancer Center SPORE in Head and Neck Cancer
Scott M. Lippman, M.D. Purpose and Intent: The goal of the M.D. Anderson Cancer Center SPORE in Head and Neck Cancer is to facilitate innovative translational research in the biology, detection, prevention and treatment of head and neck cancer, leading eventually to the elimination of this disease. Our dedicated collaborative researchers will accomplish this goal by effective integration of laboratory, epidemiologic, and clinical research, which will lead to changes in clinical practice that will provide innovative prevention and treatment strategies and improve outcome for patients with this disease. Advances have been made in recent years through the use of strategies such as chemoprevention for the reversal of oral premalignant lesions and the prevention of second primary tumors, and combination chemotherapy/radiotherapy for advanced head and neck cancer in order to avoid radical surgery and preserve organ function. These advances have improved quality of life in terms of cosmesis and function, but they have done little to improve survival. Head and neck cancer is the sixth most common cancer worldwide, and unfortunately, its incidence seems to be increasing as tobacco products become more widely used. Major challenges remain in developing effective chemopreventive strategies to prevent cancer development, and in developing effective therapeutic strategies integrating molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve survival. This application was designed to address these challenges.
Project 1 In a series of cases with oral cavity cancers (n=300) and oral premalignant lesions (n=100), we propose an integrated molecular epidemiologic approach to correlate genetic susceptibility phenotype and genotype data in lymphocytes, and to extend these findings to biopsies and surgical specimens of premalignant and malignant oral cavity lesions. We will measure functional nucleotide excision repair (NER) capacity using the host cell reactivation assay with plasmids damaged by benzo[a]pyrene, and establish frequencies of select polymorphisms in DNA repair genes implicated in the nucleotide excision repair pathway (ERCC1, XPC, XPD/ERCC2, XPF/ERCC4). We will correlate genotype with functional NER activity. We hypothesize that individuals with "adverse" genotypes of the nucleotide excision repair pathway will exhibit poorer DNA repair capacity. In surgical specimens from the two case groups, we will assess LOH at 3p14 and 3p21, 9p21 and 17p13 and correlate with epidemiologic covariates and constitutional markers of genomic instability (DNA repair capacity, genotypes). Finally, we will identify a subset of 100 patients with oral cavity cancer for whom we will assess BPDE-induced specific chromosomal hotspots (3p21, 3p14) in lymphocyte cultures for comparison with tissue LOH data. We hypothesize that there will be concordance in the severity of site-specific chromosomal lesions in target and surrogate tissue. The overarching goal of these studies is to determine if the lymphocyte markers that we have already shown to be significant predictors of cancer risk (DNA repair capacity and DNA repair gene polymorphisms) are an adequate reflection of genetic events in the target organ tissue. This finding will have substantial implications for future large-scale population-based molecular epidemiology studies. The long-term application to risk assessment and, therefore, cancer prevention and early detection is considerable.
Project 2 The major cause of death from squamous cell cancer of the head and neck (SCCHN) is progressive growth with invasion and metastasis. The design of effective new therapies against SCCHN requires a better understanding of the process of metastasis. Recent data show that the progressive growth and metastasis of SCCHN are dependent on the development of new vasclature, i.e., angiogenesis. We hypothesize that the angiogenesis and hence aggressive nature of human SCCHN is due to an imbalance between proangiogenic (IL-8, bFGF, VEGF, MMP-9) and antiangiogenic (IFN-a/-b) molecules; restoration of this balance by systemic administration of an optimal dose of IFN is expected to inhibit angiogenesis and, therefore, progression and metastasis of human SCCHN. IFN-a and -b negatively regulate the activity of NF-kB family transcription factors. The absence of IFN-b (in the tumor and surrounding tissues) leads to enhanced activity of NF-kB and hence enhanced expression of IL-8 and MMP-9 along with increased angiogenesis. Restoration of IFN-a should therefore inhibit angiogenesis and, hence, progression of SCCHN. We shall determine whether increased microvessel denisty and elevated expression of bFGF, IL-8, VEGF, MMP-9, and reduced expression of IFN are found in surgical specimens of human SCCHN from patients with more advanced disease or poorer treatment outcomes. We also will use a relevant orthotopic (tongue implantation) nude mouse model to determine if metastatic cell line variants in this model demonstrate NF-kB activation, and/or elevated expression of bFGF, IL-8, VEGF, MMP-9, and reduced expression of IFN. Since neoplastic angiogenesis is associated with a decrease in tissue level of IFN (a and b), we will determine if systemic administration of an optimal dose of IFN can inhibit angiogenesis of human SCCHN implanted orthotopically in nude mice. Finally, we will evaluate the antiangiogenic activity of pegylated IFN in the preoperative setting for patients with SCCHN. Information gained through these studies will contribute to our understanding of angiogenesis in human SCCHN as it relates to invasion and metastasis on the systemic, cellular, and molecular levels; this is essential for the design of effective anti-angiogenic therapy and rapid translation to the clinic for the benefit of patients.
Project 3 Growth factors and their receptors are essential for epithelial cell function. Abnormalities in expression of epidermal growth factor receptor (EGFR) and its downstream signaling pathways contribute to progression, invasion and maintenance of the malignant phenotype in human head and neck cancers. Agents directed against EGFR are promising biologically-based treatments. This project is designed to determine whether the EGFR kinase inhibitor ZD1839 (Iressa) can suppress the activity of EGFR, thereby inhibiting the downstream signaling pathways thought to be important in head and neck cancer carcinogenesis and halting disease progression. Data suggest that EGFR over-expression may be closely linked with c-Src and Pak1 kinases in head and neck cancer, and that ZD1839 may block EGFR-linked stimulation of these kinases. These data support the hypothesis that activation of the EGF receptor family stimulates the Src and Pak1 signaling pathways, leading to increased cell survival, mitogenesis, motility and development of malignant phenotypes of head and neck cancer cells. We hypothesize that these phenotypic changes can be suppressed or reversed by ZD1839. To address these hypotheses, we propose the following specific aims:
These studies will delineate the mechanisms through which EGFR regulates growth, motility and survival of head and neck cancer cells and will provide a novel rationale for therapy of preneoplastic and malignant human head and neck tumors with an EGFR inhibitor. This work is designed to develop a novel strategy for prevention of head and neck carcinogenesis and establish the utility of mechanism-based signaling endpoints in prognosis of head and neck cancer and in evaluation of the biologic response to ZD1839.
Project 4 Premalignancies of the oral cavity and oropharynx have a high risk of progression to invasive squamous carcinomas. Our biochemoprevention studies suggest that these sites are tremendously resistant to our most active agents, including cis-retinoic acid, interferon-a and a-tocopherol; while clinical and pathologic response rates approach 80% in the larynx, there is a response rate of only 15% in the oral cavity. We hypothesize that over-expression of the wild-type p53 tumor suppressor gene in premalignant cells will induce apoptosis, allowing for re-population with epithelial cells of normal genotype and phenotype. Clinical studies show that adenovirus-mediated p53 gene transfer induces apoptosis in squamous cell carcinoma; apoptosis is observed without dose-limiting toxicity and independent of endogenous p53 genotype; importantly, non-malignant fibroblasts and epithelial cells remain unaffected. To address the hypothesis that over-expression of wild-type p53 will reverse the malignant process, we propose to conduct a clinical trial with an adenovirus vector encoding Ad5CMV-p53 (RPR/INGN 201) administered via intramucosal injection and multiple oral rinses to patients with oral premalignant carcinoma. The study will be conducted as a Phase I/II study, with determination of maximum tolerated dose and effect of p53 gene transfer in reversing the clinical and histologic appearance of oral and oropharyngeal premalignancies to be evaluated in Specific Aim 1. In Specific Aim 2, we will determine the effect of p53 gene transfer on expression of molecular biomarkers of p53 activity in preneoplastic lesions of the oral cavity and oropharynx. We will determine the relationship between expression of the Coxsackie adenovirus receptor (CAR) expression and p53 induction in response to adenovirus p53 gene transfer. Other biomarkers to be studied include MDM2, MDMX, ARF, bcl-2, bax, and apoptotic index. In Specific Aim 3, we will determine the role of the p53 inhibitors MDM2 and MDMX in the development of SCCHN and in response to adenovirus p53 gene transfer; for these studies, we will correlate MDM2 and MDMX levels with p53 levels in tissue biopsies from patients with oral premalignancies enrolled in the clinical trial and in archival tissue samples from patients with SCCHN. Finally, we will conduct laboratory studies to begin to evaluate the therapeutic potential of alterations in MDM2 and/or MDMX in SCCHN. The data collected in this project will expand our understanding of the role of p53 and the p53 inhibitors MDM2 and MDMX in progression of oral cavity and oropharynx premalignancies and development of squamous cell carcinoma of the head and neck.
Project 5 Strategies for improving the therapy of head and neck cancer should be investigated intensively in order to reduce the morbidity and mortality rates. Induction of selective apoptosis in cancer cells appears to be an effective approach to cancer therapy. We propose to use agents and combinations of agents that can induce apoptosis in head and neck cancer cells in studies designed to assess their potential for therapy of head and neck cancers. Hypothesis: Combinations of retinoids (4HPR and MX335) and farnesyl transferase inhibitor (e.g. FTI SCH66336) have potential to act additively or synergistically to induce apoptosis pathways and enhance cell death in vitro and in vivo and can be effective in the therapy of head and neck cancers. The objectives are: 1) To identify effective agents or combinations thereof among retinoids and FTI that induce apoptosis in vitro in head and neck cancer cells. 2) To analyzed selected agents for their ability to exert therapeutic effects in an animal model of human HNSCC. 3) To conduct a clinical trial in SCCHN patients using a 4HPR/SCH 66366 combination. To accomplish these objectives we shall pursue the following specific aims: 1) To determine the ability of the synthetic retinoids 4HPR and MX335 and the FTI SCH66336 used as single agents and in combination to inhibit the growth, induce apoptosis, and suppress pro-angiogenic activities in several established HNSCC cell lines and normal oral keratinocytes and explore the mechanisms underpinning possible interactions among these agents. 2) To determine the ability of 4HPR, MX335, SCH66336 and their combinations to inhibit the growth of human HNSCC implanted subcutaneously in athymic nude mice and to investigate the mechanisms of the in vivo activity, especially those related to inhibition of cell growth, induction of apoptosis, and inhibition of angiogenesis. 3) To conduct a Phase Ib randomized translational study of 4HPR in combination with SCH66336 in patients with advanced head and neck cancer. Specifically, to estimate the modulation by 4HPR/SCH66336 combination of biological endpoints across four randomly assigned dose levels and to assess the toxicity profile of the 4HPR/SCH66336 combination across four different dose levels. If the results of the 4HPR/SCH66336 combination are favorable then the understanding the biologic interaction between these two promising agents would be important for selecting an appropriate dose combination for future Phase II trials. Furthermore, those biomarkers that are found to be modulated by the 4HPR/SCH66336 combination could be used as intermediate biomarkers in such studies.
Core A The Administrative Core is critical to the success of the SPORE. The specific objectives of the Administrative Core are:
The Administrative Core will be led by Drs. Waun Ki Hong, Gary Clayman and Reuben Lotan, all of whom has extensive expertise in the successful and productive management of large, multidisciplinary research programs. The Core leaders maintain good working relationships with members of the National Cancer Institute and National Institutes of Health and are very familiar and in full compliance with all policies and procedures required of NCI- and NIH-funded research programs.
Core B The Biostatistics and Data Management Core for the University of Texas M.D. Anderson Cancer Center Head and Neck SPORE will be a comprehensive, multi-lateral resource for data acquisition and management, designing clinical and basic science experiments, developing innovative statistical methodology, statistical analysis, and publishing translational research generated through the head and neck SPORE program. The Biostatistics and Data Management Core will incorporate sound experimental design principles within each project that will increase the clarity and enhance interpretability of study results. Each project will be provided with tailored analyses, accompanied by novel statistical development as necessary, to reveal apparent and hidden relationships among data. The Biostatistics and Data Management Core will provide expertise in the design of an integrated data management system to facilitate communication among all projects and cores. This process includes prospective data collection, data quality control, data security, and assurance of patient confidentiality. The Biostatistics and Data Management Core will collaborate with all project investigators to facilitate the timely publication of all data collected under the SPORE research program. The main objectives of the Biostatistics and Data Management Core are:
Core C Effective tissue procurement and utilization is vital for meaningful translational research activities. The Tissue Procurement and Pathology Core will work with each SPORE project and the Biostatistics and Data Management Core to ensure efficient and highly-coordinated procurement, use and storage of human tissue samples. The Core will obtain and maintain a repository of tissue samples (including tumor tissue, premalignant tissue, adjacent non-malignant tissue, peripheral blood lymphocytes and surrogate tissues) for laboratory use, with an effective coding system for all laboratory specimens to ensure patient confidentiality and prevent experimental bias. Continuous communication between the surgeons, research nurses, biostatisticians and pathologists, as well as standardized operating procedures for activities will provide for optimal tissue collection and accurate processing, analysis and storage of each sample. Thus, the functions of the Tissue Procurement and Pathology Core are to facilitate acquisition, preservation, analysis and dispersal of clinical samples and to provide histopathologic characterization of tumor tissues for all project investigators. The Tissue Procurement, and Pathology Core has the following objectives:
Developmental Research Program The Developmental Research Program is designed to provide funding to initiate promising translational studies with a focus on head and neck cancer. High priority will be given to projects that will generate clinically-relevant hypotheses aimed at reducing the incidence, morbidity or mortality of head and neck cancer or improving the quality of life of patients with head and neck cancer. At least annually, proposals for innovative translational research in head and neck cancer will be solicited throughout all institutions in the Texas Medical Center. It is anticipated that some applicants will be without extensive experience in preparing successful research proposals; therefore, the Director and Co-Director will help investigators formulate specific aims and research plans that are translational in nature, with realistic and appropriate budgets. Thus, in addition to developing promising research projects for the SPORE program, the Developmental Research Program also will be a major educational activity that will further enhance the initiation and development of innovative translational research concepts in head and neck cancer. The SPORE Executive Committee will screen proposals for appropriate SPORE qualifications using objective criteria. The selected proposals then will undergo scientific review and prioritization by members of the SPORE External Scientific Advisory Board; final selection of the research projects to be funded will be made on the basis of these reviews. A two-year funding period will be allowed, with allocation of funds for the second year to be made after satisfactory review of a thorough progress report from the awardee. Additional funding may be granted if it is felt that an additional year of work will lead to independent peer-reviewed funding and/or lead to significant enhancement in treatment or prevention of head and neck cancer; requests for this additional funding will be very carefully reviewed by the SPORE Executive Committee and External Scientific Advisory Board. As part of our continuing efforts to expand head and neck cancer research at M.D. Anderson Cancer Center and in anticipation of this SPORE application, developmental research projects were solicited within our institution in early 2001; the four projects considered to be of highest potential and consistent with the translational focus of the SPORE are included here and represent those that will be reviewed for funding consideration to begin in Year 1 of the SPORE program. These projects illustrate the breadth and depth of interest in head and neck cancer translational research at our institution.
Career Development Program The Career Development Program is designed to provide training and guidance for academic physician-scientists, clinician-investigators and laboratory-based scientists who wish to dedicate their efforts to translational research in the area of diagnosis, prevention and treatment of head and neck cancer. In order to meet this goal, the Career Development Program has developed these specific objectives:
We will achieve these objectives through a strong mentorship program in which awardees will be instructed in the principles of clinical and epidemiological head and neck cancer, combined with basic science studies of cell biology and cancer biology. The Career Development Program will recruit senior medical or laboratory-based post-doctoral fellows and junior faculty who wish to develop a career in translational research focussed on head and neck cancer; in addition, established senior faculty who wish to re-direct or extend their ongoing research programs will be eligible for participation. |
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