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University of Michigan SPORE in Head and Neck Cancer University of Michigan Health System Henry Ford Health System Ann Arbor Veterans Affairs Medical Center Overall Abstract A comprehensive multidisciplinary translational research program is proposed that will significantly improve the diagnosis, treatment and prevention of head and neck cancer while decreasing morbidity and mortality associated with this disease. The emphasis in this Specialized Program of Research Excellence (SPORE) is the development of innovative organ preservation treatment approaches that will reduce patient morbidity and to develop, test and incorporate sound prevention strategies with systemic treatment approaches that will address distant metastases and second primary cancers. Five proposed projects and three developmental projects will explore the molecular basis for chemotherapy and radiation treatment decisions (Projects 1, 2, 5) and the risk of distant metastases (Projects 3, 4, 5) or tumor recurrence / second primary cancer (Project 3). The overall hypothesis of this SPORE is that future advances in the treatment and prevention of head and neck cancer will be based on better understanding of specific molecular and genetic alterations characteristic of individual tumors. Based on this hypothesis, more specific and less morbid treatment regimens will be developed and tested that optimize organ preservation, prevention of recurrence and therapy of disseminated disease. Strong emphasis in this SPORE is placed on career development and pilot research project development to ensure ongoing innovation and increases in the numbers of new investigators dedicated to head and neck translational research. A limited number of critical infrastructure cores are also proposed. This Head and Neck SPORE is a fully integrated component of the University of Michigan Comprehensive Cancer Center. We propose extensive use of Cancer Center core facilities, clinical and laboratory resources and investigators, and draw heavily on experienced Cancer Center leadership. Superb teams of experienced clinical / basic collaborators combined with high institutional commitment and priority, and extensive patient resources provide an outstanding research environment that will ensure success in achieving overall SPORE goals.
Project 1: Optimizing Gemcitabine-Mediated Radiosensitization Gemcitabine (dFdCyd) is an analog of cytosine arabinoside with clinical activity against a variety of solid tumors. Based on our preclinical studies demonstrating that dFdCyd is a potent radiation (RT) sensitizer, we designed a novel clinical trial combining dFdCyd with RT for the treatment of patients with advanced head and neck cancers. This trial produced approximately 80% pathologic complete responses, but there was substantial toxicity. The long term goal of this proposal is to understand the mechanism of dFdCyd-mediated radiosensitization and to use this information, in combination with data from animal models and biopsies from patients' tumors, to increase the efficacy of dFdCyd as a radiation sensitizer. This goal will be addressed through 3 specific aims: Specific Aim 1 is to elucidate the mechanism by which dFdCyd increases radiation-induced apoptosis. Our preliminary data establish that apoptosis plays a critical role in maximizing sensitization. We propose to dissect the apoptotic pathways to determine the molecular mechanism by which sensitization is achieved. Specific Aim 2 is to assess the effect of radiation on dFdCyd metabolism, clearance, and efficacy in vivo. A unique strength of this aim is that the effect of radiation on the presence of dFdCyd and its metabolites will be measured in vivo using MRS. We hypothesize that dFdCyd metabolism within tumors and normal tissues is affected by radiation, and that an understanding of the changes in metabolism will influence the design of clinical trials. Specific Aim 3 is to carry out new clinical trials based on our laboratory and clinical experience using dFdCyd. In Specific Aim 3A, we will carry out a phase I trial using twice-weekly dFdCyd administered during the last 2 weeks of radiation. This trial is derived directly from our preclinical and clinical data. In Specific Aim 3B, we will carry out a phase I trial using intraarterial carotid dFdCyd in combination with radiation. This approach also has a high likelihood of increasing the therapeutic index by limiting the exposure of the contralateral tissues to dFdCyd and of being superior to IA administration of cisplatin with radiation (RADPLAT), which produces substantial systemic toxicity. These clinical trials will include, as have our past studies, biopsies to assess the content of dFdCyd metabolites. We feel our preliminary data, research team, and record for translating preclinical findings to the clinic suggest that this proposal is likely to generate data which will improve the outcome of treatment of patients with unresectable head and neck cancer.
Project 2: Utilizing Molecular Markers to Predict Chemoradiation Response in Advanced Laryngeal and Hypopharyngeal Cancer Prior work on patient samples and tumor cell lines has shown that overexpression and mutation of p53 and low expression of the apoptosis-blocking proteins Bcl-xL and Bcl-2 correlate with chemotherapy response and successful organ preservation using sequential chemoradiation. The next step is to prospectively evaluate these molecular markers in clinical trials for their predictive value for chemotherapy response, organ preservation, and survival in order to select patients properly and avoid unnecessary morbidity and therapeutic redundancy. These data will allow the rationale design of future treatment paradigms where patients are selected for optimum therapy based upon the molecular profile of the tumors. A comprehensive research program is proposed to investigate the role of the p53 tumor suppressor gene and the Bcl-2 family of genes in the chemo/radiosensitivity of advanced laryngeal and hypopharyngeal squamous cell carcinoma. The hypothesis to be tested is that a combination of p53 mutation status and expression of the Bcl-2 family of genes determines the mechanism of cell death and response to chemoradiation regimens. Concurrent with the clinical investigations, in vitro studies will be performed to directly assess the impact of manipulation of p53 and Bcl-2 status upon chemotherapy and radiation sensitivity. We plan to test our hypothesis by executing the following specific aims: (1) To prospectively determine if a combination of apoptosis gene markers (p53, Bcl-2, Bcl-xL) predict response to neoadjuvant chemotherapy, organ preservation and survival in patients with advanced laryngeal and hypopharyngeal cancer; and (2) To test the hypothesis that cisplatin and radiation resistance in tumor cells can be overcome by direct inhibition of apoptosis-blocking genes using gene transfection strategies and small molecule inhibitors of Bcl-2 and Bcl-xL in in vitro model systems. Furthermore, we will test the hypothesis that transfection of dominant-negative p53 mutations will enhance the sensitivity of HNSCC cell lines to radiation and chemoradiation.
Project 3: Molecular Markers, Health Behaviors and Comorbidities as Predictors of Tumor Recurrence, Survival and Quality of Life in Head and Neck Cancer A variety of past studies have provided insightful, but varied information about the predictors of tumor recurrence, survival, and quality life in patients with head and neck cancer, however, none of the studies have prospectively assessed the nature, relative strength, and interrelationships of these factors together as predictors of recurrence, survival, and quality of life. The specific aims of this study are to test the hypotheses that: 1) health behaviors (smoking and alcohol use), comorbidities, and molecular markers (tumor p53, serum human papilloma virus (HPV-16), and serum vascular endothelial growth factor (VEGF)) are predictors of tumor recurrence; 2) health behaviors, comorbidities, and molecular markers are predictors of survival; 3) health behaviors and comorbidities are predictors of quality of life; and, 4) serum HPV-16 and serum VEGF are sensitive and specific tests for the identification of tumors with high levels of tumor HPV-16 and tumor VEGF. This observational, longitudinal study will be conducted at three hospitals and enroll 1391 patients. Information on health behaviors, clinical characteristics, treatment modalities, and demographics will be collected through patient surveys and hospital records. Serum will be collected every 3 months for assessment of levels of HPV-16 and VEGF. Tumor tissue will be collected at time of initial tumor biopsy or tumor resection and analyzed for p53, HPV-16, VEGF and for construction of tissue microarrays as a SPORE resource for future molecular epidemiologic studies. Independent variables of interest will include health behaviors, comorbidities, and molecular markers while controlling for tumor site and stage, treatment modalities, and demographic factors. Dependent variables will include 1) tumor recurrence, 2) survival, and 3) quality of life. Stratified and multivariate analyses for cross-sectional and cohort data (e.g. survival data) will then be performed (e.g. Cox proportional hazard models). Newly developed advanced statistical techniques will be used to jointly model the longitudinal biomarkers and survival and tumor recurrence. Advanced techniques for longitudinal data will be used to analyze the quality of life data. The sensitivity and specificity of serum HPV-16 and VEGF will also be calculated in a cohort of patients by correlating each serum marker to its respective tumor marker. The results of this study are expected to directly translate into improvements in detecting tumor recurrence, improving survival, and increasing quality of life for head and neck cancer patients and will provide useful information about screening and prevention services needed by this population.
Project 4: Galanin and Galanin Receptors as Markers of Tumor Progression In spite of advances in treatment options for patients with head and neck cancer the survival rates have not changed appreciably in nearly thirty years. A subset of patients at each stage of disease fails to respond regardless of the therapy they receive. The fraction of patients whose tumors relapse quickly and cause death is significant even at Stage I and increases significantly with each higher stage. Thus, although 90 percent of stage I patients can be cured either by surgery or radiation therapy, 10 percent relapse and die. For patients at Stage II, the fraction of aggressive tumors rises to 30%, to 50% at Stage III and to >70% at Stage IV. Thus, the early identification of most aggressive neoplasms is an important goal so that suitably aggressive therapy can be employed for this most lethal group of tumors. It is likely that survival will be prolonged and some of these patients will be cured when disseminated disease is microscopic. Furthermore, the identification of mechanisms of aggressive tumor behavior will also provide new targets for therapy. We postulate that specific genetic changes determine the biological behavior of individual tumors and we have focused our research on genetic markers associated with aggressive tumor behavior and response to therapy. We previously reported that loss of chromosome 18q develops with tumor progression and is associated with significantly decreased survival in head and neck cancer patients. Recently we discovered that tumors with loss of chromosome 18q23 also have loss of expression of galanin receptor 1 (GALR1), which maps to 18q23, and this is accompanied by gain of expression of another receptor, galanin receptor 2 (GALR2). GALR1 and GALR2 are G-protein coupled receptors that signal by different G-protein pathways. GALR2 is a growth factor in small cell lung cancer. Our preliminary results show that galanin, the neuropeptide ligand that binds to these receptors, and GALR1 are expressed in normal keratinocytes, but GALR2 is not. Furthermore, anti-galanin antibody causes growth inhibition of galanin secreting tumor cells. Thus, we postulate that altered expression and function of galanin receptors identify an aggressive subset of head and neck tumors and will provide a novel target for intervention. We will extend our laboratory findings to patients' tumors to test the value of the GALRs as markers to detect aggressive neoplasms and to determine if GALR alterations predict response to therapy. We will also investigate the mechanisms of galanin signaling in HNSCC. This research should lead to identification of aggressive subsets of head and neck tumors and may result in the development of new adjuvant treatment strategies for the most lethal subset of head and neck cancers.
Project 5: The Use of Tetrathiomolybdate as an Anti-Angiogenic Therapeutic Agent Against Human Squamous Cell Carcinoma Angiogenesis is a physiologic process defined as the formation of new blood vessels from pre-existing vasculature. Overwhelming evidence illustrates that new vessel formation is the rate limiting step in tumor growth and metastasis. Inhibition of angiogenesis, therefore, could have far reaching implications in the treatment of head and neck cancer. Due to the complexity of this process, any global disruption in tumor angiogenesis would require innovative strategies that inhibit multiple steps along the angiogenesis pathway. Our preliminary studies reveal that copper suppression therapy utilizing a novel compound, Tetrathiomolybdate ( TM ), is one such promising approach. In multiple, in vivo and in vitro investigations utilizing breast, head and neck, and Lewis lung carcinoma, TM has dramatically inhibited angiogenesis, halted tumor growth, worked synergistically with cytotoxic therapy and prevented microscopic tumors from obtaining the blood supply needed to become clinically visible. TM's mechanism of action is achieved by sustained inhibition of NF-kappaB, a nuclear transcription factor with receptors found in the promoter regions of multiple pro-angiogenic cytokines. We hypothesize that NF-kappaB inhibition results in a marked inhibition of angiogenesis and an increased responsiveness to cytotoxic therapy. We will test our hypotheses in vitro utilizing well characterized cell lines and in vivo with human tumor murine xenografts. The relationship of NF-kappaB expression with cytotoxic therapy responsiveness will be evaluated using the Veterans' Affairs Laryngeal Cooperative Study #268 tissue samples. Taken together, the information acquired in this work will be used to design a new clinical trial utilizing TM either as a chemopreventative agent for patients at high risk for recurrence or as an adjunct to improve the efficacy of existing chemo/radiation therapy regimen.
Administrative Core A broad-based and diverse translational research program that is collaborative, multidisciplinary, and interrelated requires specific administrative leadership and support to be successful. The University of Michigan Head and Neck SPORE consists of an ambitious, highly integrated and synergistic program of five major research projects, and a comprehensive program for selection, support and evaluation of pilot research projects and career development awards. An administrative shared resource is proposed to maintain the focus on the translational goals, institutional commitment and adequate infrastructure support for clinical / basic science integrated efforts. The UM H&N SPORE Administrative Core has committed significant resources for program organization, coordination, data management, computer support and management services necessary to link each project and achieve overall spore goals. This Core will act as a central information clearinghouse, and provide organization for all meetings, budgets, financial reporting, data management, quality control, activity reports, problem solving, scientific leadership, and solicitation of new ideas and faculty. The Core is responsible for program evaluation, recruitment and support of Internal and External reviewers, and administrative support and evaluation of the Developmental Research and Career Development Programs. Gregory T. Wolf, M.D., Chair of Otolaryngology- Head and Neck Surgery will function as PI and will be responsible for planning and implementation, reporting and assessment of all aspects of the SPORE Program. He has extensive experience in multidisciplinary translational research. The Core is organized to maximize oversight, investigator support, enhance patient care, and electronic data management through the use of formal seminars, meetings and reports. To ensure success, he has committed significant effort (30%) to this Core, which includes 5% on each Career and Research Development Programs. The operation of this Core will enhance and facilitate the unqualified success of this SPORE effort and thereby have a direct, favorable impact on the treatment, morbidity and mortality of head and neck cancer.
Biostatistics Core The Biostatistics Core consists of personnel with statistical expertise. The goal of the Biostatistics Core is to collaborate with SPORE investigators and other core resource scientists to enhance the quality of the research undertaken in the University of Michigan Head and Neck SPORE. The Core personnel have been chosen because of their expertise in relevant areas of Biostatistics and because of their experience and knowledge of Head and Neck cancer. Biostatistics core personnel will collaborate with every one of the five proposed projects, will interact with the other cores and also will expect to interact with all funded development awards, and thus this core is crucially important to the SPORE. Personnel from the core will interact with the investigators in all stages of the research, beginning with the formulation of the research question, through the experimental design stage and data collection stage, to data analysis and interpretation, to the writing of reports and dissemination of results. Two areas where biostatistical expertise is indispensable are in experimental design and data analysis. It will be apparent from this proposal that Core personnel have played a significant role in designing the proposed experiments and in planning the data analysis. The Specific Aims of the core are to:
Career Development Program Translational research in head and neck cancer is critically needed to enhance applications of the knowledge gained through the rapid expansion of our understanding of the molecular basis of cell growth and development. A comprehensive faculty career development program is proposed to meet the urgent need for increased number of clinicians and basic scientists devoted to head and neck cancer research. Although some of this need has been addressed through NIH T32 training grants for post doctoral fellows, transition to an independent, funded research career in head and neck cancer for full time faculty has been difficult. Direct funding of Assistant Professors with outstanding new translational research programs relevant to head and neck cancer is proposed to address this limitation. Focus on young faculty members will ensure attraction of new, energetic investigators, who when successful, will likely maintain a long-term research interest in head and neck oncology. A rigorous selection process is outlined that includes University-wide recruitment, strong emphasis on recruitment of women and minorities and comprehensive basic and clinical science mentoring. Close evaluation and monitoring is achieved through monthly meetings and annual internal and external review for continued funding. A major emphasis is placed on salary support for clinician scientists to ensure adequate time commitment to their SPORE research program.
Development Research Program A Developmental Research Program is proposed that will promote new ideas in basic / translational research and the development of strong, independent, collaborative clinical / basic research projects. The development of innovative approaches to head and neck cancer is a national critical need. A recognized strength of the SPORE mechanism is the ability to foster new translational ideas important to advance the field, allow development of preliminary data for future grants and promote high risk research endeavors. We appreciate this strength and propose commitment of significant resources of $150,000 ($100,000 SPORE and $50,000 Medical School) per year to support this program. Investigators are invited to submit brief (five page) proposals to the Senior Advisory Committee of the UMCCHN SPORE in response to a University-wide and selected outside institution solicitation. Responsive proposals are those requesting 1-2 years of support ($25-50,000/year) to produce pilot data sufficient to support an application for independent funding. Emphasis is placed on new investigators, trainees completing their education and established investigators new to head and neck oncology. Proposals are judged by relevance to head and neck oncology, translational significance and innovation. A comprehensive mentorship and continuing evaluation program are proposed. Three specific projects were selected by this mechanism and proposed for funding in the initial grant period. These projects were judged as particularly strong and exciting proposals to develop pilot data in molecular resonance imaging to monitor tumor response, proof of principle experiments for novel gene-therapy based highly selective chemotherapy pro-drug converting enzyme delivery, and investigations of the role of multiple DNA viruses as co-factors modulating tumor radiosensitivity.
Tissue Core Extending our understanding of the molecular events in cancer growth and progression requires detailed correlations of molecular characteristics with biologic tumor behavior and host response These data are essential to the design of new, more effective therapies, better application of conventional treatments and prevention strategies for tumor relapse. An essential prerequisite is availability of complete clinical, demographic, and treatment data that are integrated with molecular data from well-characterized human tumor and serum samples. To support the research efforts of investigators in this UM-HN SPORE program, the NCI and other SPORE programs, a comprehensive tissue procurement, processing, storage and data management system is proposed. This core represents collaborative efforts of basic scientists, anatomic pathologists, clinicians and data managers. It builds our prior experience in collecting, storing and distributing tissues among our Head and Neck Oncology Program Investigators and the experience of our UM Cancer Center Tissue and Tumor procurement Core. Detailed distribution rules and standardized processing for paraffin, imbedding, frozen storage, immunohistology, tissue microarray, and cell culture preparation are included. A detailed descriptive relational database including tumor characteristics, patient demographics, health behaviors, co-morbidities, family history, treatment and follow-up data is linked with the tumor repository data and each investigator laboratory by a Head and Neck Computer web-based Network. Flexibility is provided to meet specific needs of any project and incorporation of new technologies for future projects or collaborations with outside investigators. We have proposed a model system that will be a resource that maximizes superb tissue-clinical data availability for studying these relatively uncommon head and neck cancers by the entire NCI SPORE community.
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