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University of Michigan Head and Neck Cancer SPOREGregory T. Wolf, M.D., Principal Investigator
Overall AbstractA Specialized Program of Research Excellence for patients with cancer of the head and neck entitled “The Molecular Basis of Head and Neck Cancer Biology, Treatment and Prevention” is proposed that will significantly improve treatment results and reduce morbidity and mortality associated with this devastating malignancy. These goals will be achieved through improved understanding and application of molecular biology to the detection, prevention, treatment selection and development of new therapies for patients with head and neck cancers. Our ongoing hypothesis is that increased understanding of the molecular basis for treatment will allow more precise individualized patient selection that will result in less morbid therapy and improved quality of life, in addition to the possibility of better control of metastases and earlier detection or prevention of second primary malignancies. We propose continuation of this integrated translational research program consisting of four major projects that explore 1.) more specific treatment selection for patients likely to be cured with radiation or chemotherapy; 2.) new small molecule inhibitors of apoptosis-regulation to increase chemo/radiosensitivity; 3.) improved survival through development of sound prevention strategies; and 4.) the role of critical small molecules and chemoradiation sequencing for optimizing treatment results. These major translational projects are complemented by ongoing highly successful Career Development and Developmental Research Programs. All SPORE studies are supported by three Core Resources with demonstrated success in our initial funding period (Administration and Translational Trials Support, Biostatistics, and Tissue and Histopathology). Emphasis is placed on continued ongoing scientific review of all programs and core resources through utilization of an established Operations Committee, Senior Advisory Council and External Review Committee comprised of expert basic and clinician scientists in the field of cancer research. Strong institutional commitment in our initial funding period has been increased significantly in this renewal application to support equipment needs, our Developmental Research Program and provide increased flexibility to pursue further investigations of novel discoveries that are made as a result of these SPORE projects and collaborations. This Head and Neck SPORE is a fully integrated component of the University of Michigan Comprehensive Cancer Center. We have incorporated extensive use of Cancer Center core facilities and clinical and laboratory resources, and we 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 continued success in achieving overall SPORE goals.
PROJECT 1: METRONOMIC SMALL MOLECULE INHIBITORS OF BCL2 IN HEAD AND NECK CANCER THERAPYCo-Principal Investigators: Jacques Nör, DDS, PhD and Frank Worden, MD Head & neck tumors are highly vascularized malignancies with poor survival rates with current therapies. It is known that vascular endothelial growth factor (VEGF) is a strong inducer of tumor angiogenesis, and that VEGF enhances endothelial cell survival and resistance to treatment by upregulating the expression of Bcl-2. We have recently demonstrated that Bcl-2 functions as a pro-angiogenic signaling molecule, in addition to its well-known anti-apoptotic effect (Karl et al., 2005). Inhibition of VEGF signaling with an antibody (e.g. Avastin), or with an inhibitor of one its receptors (e.g. PTK787) results in selective ablation of tumor blood vessels and inhibition of tumor growth. These results demonstrate that the VEGF/Bcl-2 pathway is critical for the maintenance of tumor vasculature. Structure based 3D-database searching led to the development of novel small molecule inhibitors of Bcl-2 (TW-37 and TM-1252). We have demonstrated that TW-37 induces apoptosis of head & neck tumor cells and neovascular endothelial cells (but not dermal fibroblasts) in vitro, and that TW-37 is anti-angiogenic in vivo (Zeitlin et al., 2006). This work demonstrated that a small molecule inhibitor of Bcl-2 represents a novel class of drugs that induces tumor cell apoptosis and is anti-angiogenic, two distinct and perhaps synergistic anti-tumor effects. However, we do not know the effect of a small molecule inhibitor of Bcl-2 on the resistance of head & neck tumors to radiation therapy and to conventional chemotherapy, and what is the better treatment sequence and timing. The broad long-term goals of this translational project are to understand the effect of therapeutic inhibition of Bcl-2 on the clinical outcome of patients with head & neck cancer. The objectives of this application are to evaluate the effect of a small molecule inhibitor used in a metronomic regimen (low dose, high frequency) in combination with radiation therapy and Cisplatin on angiogenesis in vitro and in vivo, and on the growth of head & neck tumors in vivo. We plan to accomplish these objectives by studying mechanisms involved in the process of small molecule inhibitor of Bcl-2-mediated endothelial cell and tumor cell apoptosis, when used in combination with ionizing radiation and chemotherapy. The SCID Mouse Model of Human Angiogenesis and in vivo bioluminescence will be used to evaluate the effect of timing and sequence of treatment on angiogenesis and tumor growth. And a Phase I clinical trial will be conducted in patients that were previously treated with radiation therapy and standard chemotherapy to begin evaluation of the safety and efficacy of a small molecule inhibitor of Bcl-2 for treatment of head & neck cancer. The knowledge generated here will enhance our understanding about the function of Bcl-2 in head & neck tumor angiogenesis and growth, and will demonstrate if therapeutic blockade of Bcl-2 function affects resistance to ionizing radiation and chemotherapy.
PROJECT 2: THERAPEUTIC POTENTIAL AND MECHANISM OF ACTION OF POTENT, SMALL MOLECULE INHIBITORS OF THE P53-MDM2 INTERACTION FOR THE TREATMENT OF HEAD AND NECK CANCERCo-Principal Investigators: Shaomeng Wang, PhD and Carol Bradford, MD Cisplatin (CDDP) is a primary agent for the treatment of head and neck squamous cell cancers (HNSCC). During the previous funding period, our group has established that HNSCC cells resistant to CDDP are characterized by high expression of Bcl-xL and wild type p53. Based upon our data, we hypothesize that agents designed to inhibit Bcl-xL or activate p53 function can be highly effective strategies for the treatment of CDDP-resistant HNSCC. To date, we have evaluated a small-molecule inhibitor of Bcl-xL ((-)-gossypol) as a potential novel therapeutic agent for the treatment of HNSCC. Our in vitro and in vivo studies have formed the scientific basis for a future clinical trial of (-)-gossypol in collaboration with Ascenta Therapeutics and the National Cancer Institute. In this new SPORE project, we propose to test a novel therapeutic strategy to target CDDP-resistant HNSCC cells with wild-type p53 status using a potent and specific small-molecule inhibitor of the MDM2-p53 interaction. In HNSCC cells with wild type p53, the function of p53 is effectively inhibited by its endogenous cellular inhibitor, the MDM2 (or HDM2) protein. MDM2 is transcriptionally activated by p53 and in turn, inhibits p53 activity through multiple mechanisms mediated by direct binding to p53. MDM2 thus functions as a potent and highly effective endogenous inhibitor of p53. We hypothesize that blocking of the interaction between MDM2 and p53 using a potent small-molecule inhibitor can effectively reactivate p53 function in HNSCC cells with wild type p53, which will lead to cell cycle arrest and apoptosis. Design and development of non-peptide, drug-like, small molecule inhibitors to target the MDM2-p53 interaction is an exciting and new therapeutic strategy for the treatment of CDDP-resistant HNSCC with wild type p53. Based upon the high-resolution crystal structure of MDM2 in complex with the p53 peptide, we have designed a class of highly potent, non-peptide, small-molecule inhibitors of the MDM2-p53 interaction using an effective structure-based strategy. The most potent small-molecule inhibitor has a Ki value of 2 nM binding to MDM2 protein, 1000-times more potent than the natural p53 peptide. Using a potent lead compound (MI-63) and its inactive control analogue, we have already demonstrated that MI-63 is highly effective in inhibition of cell growth and induction of cell death in HNSCC cancer cell lines with wild-type p53 and displays an excellent selectivity over HNSCC cancer cell lines with mutated p53 status. Moreover, using an isogenic cell line transfected with Bcl-xL protein, we also show that overexpression of Bcl-xL has no effect upon the activity of potent MDM2 inhibitors, in contrast to CDDP. Based upon our preliminary results, we hypothesize that a potent and specific small-molecule inhibitor of the MDM2-p53 will be developed as a new and highly effective therapy for the treatment of HNSCC, either as a single agent or in combination with other therapies.
PROJECT 3: SMOKING ABSTINENCE, MOLECULAR MARKERS AND SOY ISOFLAVONE CHEMOPREVENTION IN HEAD AND NECK CANCERCo-Principal Investigators: Gregory Wolf, MD, Sonia Duffy, PhD, RN, and Stephen Gruber, MD, PhD, MPH In chemoprevention of head and neck squamous carcinoma (HNSCC), new approaches must consider the sustained epigenetic effects of tobacco use on host molecular mechanisms and identification of novel agents with limited toxicity and acceptable therapeutic ratio. Smoking and nutrition have been identified as significant factors that contribute to carcinogenesis and prognosis of these cancers. Epigenetic CpG island methylation in the tumor promoter gene p16 is frequent in HNSCC and in the mucosa of smokers, premalignant dysplastic tissue and in non-cancerous tissue adjacent to proven malignancies suggesting an important role in early carcinogenesis and second primary malignancy. An important downstream target of p16 that may play a central role in HNSCC carcinogenesis is COX-2. COX-2 over expression is common in premalignant and malignant mucosa and is associated with smoking and chronic inflammation. When blocked, COX-2 decreases tumor growth and invasiveness. COX-2 is influenced by EGFR signaling and p16 inactivation which are commonly perturbed in HNSCC. We propose to identify frequency of gene methylation for p16 and 3 other candidate genes, gene expression alterations and related serum biomarkers associated with clinical outcome using our extensive retrospective tissue and clinical data resource. We will prospectively validate and expand these data and determine specific effects of a tailored smoking cessation program on modulation of identified biomarkers. A Phase II trial is proposed to determine if preoperative soy isoflavones can modulate these markers. Soy isoflavones have been shown to reverse p16 methylation, decrease COX-2 expression and modulate VEGF, IL6, tumor proliferation, angiogenesis and apoptosis. We hypothesize that suppressor gene hypermethylation in tumor and adjacent non-tumor mucosa and associated molecular changes in downstream targets such as COX-2, VEGF, EGFR and IL6 are associated with clinical outcome and can be abrogated by soy isoflavone supplementation and smoking cessation. We will use pyrosequencing to measure methylation of p16 and three other candidate genes in pretreatment samples from both retrospective and prospective patients and correlate with outcome. We will determine expression of EGFR, COX-2, VEGF, p53 , p65, α6β4 integrin, HPV-16, Bcl-xL in tissue and levels of VEGF, IL6, HGF and 15-Ft2-isoprostane in serial serum and saliva samples from our prospective patients. This comprehensive proposal will investigate the molecular rationale for future soy isoflavone and smoking cessation prevention trials and identify intermediate molecular endpoints. These data will help define high risk patients according to biomarkers and smoking status who might benefit most from chemoprevention. Studies of upregulated gene profiles associated with tumor suppressor gene hypermethylation may identify new target genes for future study.
PROJECT 4: INTEGRATION OF EGFR INHIBITORS WITH RADIOCHEMOTHERAPYCo-Principal Investigators: Mukesh Nyati, PhD and Avraham Eisbruch, MD The development of organ-conserving treatment for locally advanced head and neck cancers shifted the paradigm for treatment. A decade ago, we developed the strategy of selecting patients for chemoradiotherapy or for laryngectomy based on their response to a single cycle of chemotherapy. This approach results in 3-year cause-specific survival and laryngeal preservation rates of 87% and 70%, respectively. However, chemoradiation is associated with an increased rate of mucositis and dysphagia compared with radiotherapy alone. The long-term goal of this application is to preserve a high rate of larynx preservation while decreasing the toxicity of treatment by using cetuximab-radiation instead of chemoradiotherapy in patients selected to benefit from this approach. These goals will be achieved through 3 specific aims. Specific Aim 1 is to decrease the toxicity of larynx-preserving treatment by using cetuximab-radiation in place of chemoradiation in appropriately selected patients. In Aim 1A we propose to extend our current strategy in a phase II study of cetuximab-radiation for patients who would previously have received chemoradiation: those responding to a cycle of chemotherapy. In Aim 1B, we propose to assess tumor biopsies in the patients who respond to a cycle of chemotherapy and then receive cetuximab for markers of EGFR activation and downstream inhibition as possible predictors of response to cetuximab-radiation. Specific Aim 2 is to investigate the potential of established markers (Aim 2A) and to discover potential new biomarkers (Aim 2B) by assessment of phosphoproteome to predict response to cetuximab combined with radiation. Our preliminary data suggest that the extent and duration of decrease in the established markers like total EGFR, pEGFR, pSTAT3, Bcl-XL, and Ki67 correlate with response to the combination of EGFR inhibitors and radiation. In this aim, we propose to extend these studies to a total of 20 head and neck xenografts, 10 responsive and 10 non-responsive. In Aim 2B we will assess the effects of cetuximab-radiation on phosphoproteins using proteomic technology. Our preliminary data indicate that this is a promising method of identifying novel phosphoproteins that are affected by cetuximab treatment. Specific Aim 3 is to carry out preclinical studies to improve the efficacy of EGFR inhibition with radiochemotherapy. In Aim 3A, we focus on the potential importance of schedule for combining EGFR inhibition with radiochemotherapy. In Aim 3B we will focus on a novel approach toward targeting EGFR via HSP90 inhibition. Our preliminary data show that geldanamycin, an inhibitor of HSP90, accelerates the degradation of EGFR in cisplatin resistant cells, leading to both cellular toxicity and radiosensitization. We feel our preclinical and clinical team with an extensive track record in this field makes it likely that these studies will improve patient outcome.
CORE A: ADMINISTRATION AND TRANSLATIONAL TRIALSDirector: Gregory Wolf, M.D. 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 four major research projects, and a comprehensive program for selection, support and evaluation of pilot research projects and career development awards. Our Administrative Core has been a very successful shared resource that maintains the focus on the translational goals, institutional commitment and adequate infrastructure support for clinical / basic science integrated efforts. The UM H&N SPORE Administration and Translational Trials Support Core has committed significant resources for program organization, coordination, data management, community outreach, computer support and management services necessary to link each project and achieve overall SPORE goals. This Core acts as a central information clearinghouse, and provides organization for all meetings, budgets, financial reporting, data management, quality control, activity reports, problem solving, scientific leadership, and solicitation of new ideas and faculty. Oversight of day-to-day operations of the Tissue Core is provided by this Core and collaborative efforts between all core resources and SPORE projects is facilitated in this office. Patient Advocate activities and initiatives with community physicians in the SPORE Network are coordinated by this Core. 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 functions as PI and is 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 (20%) to this Core. The operation of this Core enhances and facilitates the unqualified success of this SPORE effort and thereby has a direct, favorable impact on the treatment, morbidity and mortality of head and neck cancer.
CORE B: BIOSTATISTICSDirector: Jeremy Taylor, Ph.D. 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 four 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:
CORE C: TISSUE AND HISTOPATHOLOGYCo-Directors: Thomas Carey, PhD andDouglas Chepeha, MD 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 as well as our unique panel of head and neck cancer cell lines that serve as in vitro and in vivo model systems for investigation of novel agents or mechanisms. 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, head and neck cancer cell line bank, distribution process 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, as well as cooperation with the UM Prostate SPORE. Detailed distribution rules and standardized processing for whole blood, serum, fresh tissue with proper imbedding and frozen storage, tissue in RNA Later, paraffin embedded tissue, 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’s laboratory by a secure Head and Neck web-based database called BioDBx that is interfaced with the clinical UM Health System data repository (Careweb). 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.
CAREER DEVELOPMENT PROGRAMCoDirectors: Gregory Wolf, MD and Thomas Carey, PhD 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.
DEVELOPMENTAL RESEARCH PROGRAMC-Directors: Gregory Wolf, MD and Thomas Carey, PhD Recognizing that developmental research funds are an integral part of the SPORE, we commit $50,000 per year to these endeavors. In addition, matching funds of $50,000/year are committed to this program from the University of Michigan Medical School. This represents a significant percent of the budget of the UMCC Head and Neck SPORE and reflects the continued commitment of this program to the development of innovative translational research in head and neck cancer. The focus of the Developmental Research Program is to provide investigators the ability to generate data that will become the preliminary data for an R01 grant application of an equivalent proposal. Investigators from outside the field of head and neck cancer are encouraged to apply through campus-wide announcements as well as through personal interactions with SPORE investigators. A stepwise proposal solicitation and review process has been developed utilizing NIH-type PHS 398 format applications that have been streamlined for rapid turn around of research proposals and which recognizes that these projects may have little preliminary data. Investigators may apply for support in the amount of $50,000 for a one- or two-year funding period. Since 2002 we have funded 18 developmental projects, representing a total investment of $790,000. This has resulted in over $2.6 million (direct costs) in subsequent grants, 13 manuscripts, and 4 abstracts. Dr. Gregory Wolf and Dr. Thomas Carey serve as Directors for the Developmental Research Program. Both are leaders in head and neck cancer, and hold institutional leadership positions. Together with the Senior Advisory Council, they are adept at selecting the highest quality proposals for funding and providing the necessary mentorship and support to guarantee success with this program. |
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