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Emory University SPORE in Head and Neck Cancer Dong M. Shin, M.D., F.A.C.P. Overall Abstract The Emory University Winship Cancer Institute (Emory WCI) proposes to conduct a Specialized Program of Research Excellence (SPORE) for Head and Neck Cancer (HNC). The overall goal is of the Emory WCI HNC SPORE is to improve prevention and treatment of head and neck cancer with emphasis on new discoveries, rapid translation to patients who are suffering, disability and morbidity caused by this disease. The SPORE program will consist of four (4) major translational research projects, two research cores, an administrative core, a developmental research program, and a career development program. The WCI HNC SPORE will use an interdisciplinary approach to meet its objectives by carrying out projects with co-investigators in basic, translational, and clinical science. All projects will test hypotheses about biology, prevention, molecularly and nanotechnology driven novel therapeutic approaches. The four (4) main projects are: (1) Chemoprevention with Green Tea Polyphenon E and EGFR-TKIs in HNC; (2) Targeting Death Receptors-Mediated Apoptosis for HNC; (3) Development of Novel Curcumin Analogs for the Treatment of Head and Neck Cancer, (4) Biodegradable Nanoparticle Formulated Taxol for Targeted Therapy of HNC. Each project in our SPORE program is centered on clearly defined translational objectives including pilot clinical trials (project 1, Phase I Study of Chemoprevention; project 2, biomarker studies; project 3, phase 0 trial of EF24; project 4, phase 1b clinical study) that have close interaction with the cores. The two research cores (Specimen Resources and Pathology Core, Biostatistics and Data Management Core) will assist the main research projects, developmental research projects, and career developmental investigators in performing head and neck cancer translational research. The Administrative Core will provide scientific and financial oversight for the SPORE program. We also have a strong commitment of support including space, recruitment, shared resources and matching funds from the Emory Winship Cancer Institute, Emory University School of Medicine, Woodruff Health Science Center at Emory University, Georgia Cancer Coalition (GCC), and the Georgia Research Alliance (GRA). The Emory WCI HNC SPORE investigators will work closely together as a team to achieve the goals of the program and will also interact with investigators from HNC SPORES at other institutions and other research programs to improve outcomes for head and neck cancer patients.
Project 1
Squamous cell carcinoma of the head and neck (SCCHN) is a serious healthcare problem in the United States and worldwide. Thus, the development of preventive approaches using specific natural or synthetic chemical com-pounds (chemoprevention) is highly desirable to reduce the incidence of SCCHN. Several chemo-pre-ventive regimens have been tested in preclinical and clinical settings, but no promising regimens have been well documented. In this study, we propose to use a combination of green tea polyphenon E (PPE) and erlotinib (Tarceva or OSI-774), a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), to prevent advanced premalignant lesions of the head and neck. Both PPE and EGFR-TKI have shown strong anticancer activity and chemopreventive efficacy as single agents in a variety of cancer types, including SCCHN. Our preliminary studies have shown that the combination of epigallocatechin gallate (EGCG), a major polyphenol extracted from green tea, with erlotinib synergistically inhibited the growth of SCCHN cells in vitro and in vivo. This inhibitory effect was associated with the induction of cell cycle arrest and apoptosis. Furthermore, this combination cooperatively reduced phosphorylation levels of EGFR and AKT. Both EGCG and erlotinib also regulate expression and cell surface localization of E-cadherin, suggesting that they may inhibit epithelial to mesenchymal transition (EMT) of the malignant epithelial cells. Based on these findings, we hypothesize that combined treatment with PPE and erlotinib can additively/synergistically inhibit carcinogenesis, as reflected by biomarker expression, in patients with premalignant lesions of the head and neck. To test this hypothesis we propose the following specific aims: (1) To under-stand the underlying mechanisms of the effect of combined treatment with EGCG (and/or PPE) and erlotinib on signal transduction pathways responsible for SCCHN progression and survival; (2) To conduct a phase I trial of combined treatment with PPE and erlotinib in patients with premalignant lesions of the head and neck; (3) To identify biomarkers relevant for this treatment in patients' specimens and explore correlative alterations in the proposed biomarkers with clinical and pathological findings. The clinical development of this combination of agents as a cancer preventive regimen may contribute to reducing the incidence of SCCHN. This may be further enhanced by the identification of tumor markers that can serve as indicators for treatment efficacy.
Project 2
The long-term goal of our research is to identify and develop novel and efficacious therapeutic regimens for the treatment of human cancer, particularly head and neck cancer (HNC). The current application aims specifically at targeting death receptor-mediated apoptotic pathways for the treatment of HNC, particularly metastatic HNC, through evaluating the potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or perifosine and TRAIL in combination in the treatment of metastatic HNC. Our gene array and Western blotting data indicate that highly metastatic HNC cell lines express increased levels of death receptor 5 (DR5), FADD, caspase-8 and caspase-9 and low levels of c-FLIP(L) although they exhibit undetectable levels of TRAIL and high levels of c-FLIP(S). Importantly these cell lines are highly sensitive to exogenous TRAIL treatment. Perifosine, the first oral alkylphospholipid with Akt-inhibitory activity in clinical trials, further upregulates the expression of DR5, reduces c-FLIP levels and very effectively induces apoptosis in these metastatic HNC cell lines. Based on these findings, we hypothesize that highly metastatic HNC cells retain high potential to undergo DR5-mediated apoptosis, albeit with dysregulated apoptotic signaling. Thus, agents including TRAIL and perifosine that activate the DR5-mediated apoptotic pathway may be effective in treatment of metastatic HNC. These hypotheses will be tested by accomplishing the following specific aims: 1) Determine the mechanism(s) by which perifosine and TRAIL cooperatively induce apoptosis of metastatic HNC cells; 2) Determine the efficacy of TRAIL and its combination with perifosine in an in vivo model of HNC metastasis; and 3) Determine differential expression patterns of selected genes (e.g., TRAIL, DR5, c-FLIP, and caspase-8) primarily involved in the extrinsic apoptotic pathway between primary and metastatic human HNC tissues, and evaluate their prognostic values. The accomplishment of these aims will allow us to assess the efficacy of TRAIL and its combination with perifosine in the treatment of HNC, particularly metastatic HNC, in vitro and in vivo, reveal the underlying mechanisms of perifosine and TRAIL synergism, and demonstrate the role of dysregulation of the extrinsic apoptotic pathway in HNC metastasis and its prognostic value. The results generated from this project can be directly translated to clinical practice for the better treatment of HNC patients.
Project 3
Project 3 aims to develop novel curcumin analogs for the treatment of head and neck cancer. Despite advances in targeted therapies in recent years, the long term disease-free and overall survival rates for patients with advanced disease remain poor, and treatment options for recurrent disease are very limited. However, recent advances in our understanding of the molecular basis of head and neck cancer have presented new opportunities for novel therapeutic development. The long-term goal of this application is to develop a new generation of anticancer agents that target critical survival pathways in head and neck cancers. Nature represents a rich source for drug discovery, and our strategy is to start with a safe natural product with a promising activity, such as curcumin. The demonstrated preventive and therapeutic potential of curcumin together with its attractive safety profile begs for immediate efforts to develop curcumin-based agents with improved bioavailability and enhanced anticancer efficacy. In an attempt to retain curcumin's safety profile, while increasing its potency, our preliminary studies have produced a lead compound, EF24. EF24 potently induces apoptosis of various cancer cells, inhibits tumor angiogenesis activity, and decreases tumor size in an animal model. Mechanistic studies have pointed to the NF-kB pathway as a critical molecular target for its potential therapeutic efficacy. To provide alternative candidates, the closely related analog EF31 and their water soluble analogs were synthesized and show promising biological properties. Based on these exciting findings, we propose to rapidly move these curcumin analogs into the clinic. Our study aims to (i) define the mechanism of action of EF24 and its analogs using in vitro and in vivo models, (ii) identify molecular biomarkers that response to the treatment with these drugs, (iii) determine pharmacology and toxicology profiles of these compounds to predict a NOAEL dose in humans, and (iv) select the most promising compounds for clinical evaluation in a phase 0 trial in head and neck cancer patients. Thus, our primary aim is to understand the mechanism of action of novel curcumin analogs, to define their pharmacology and toxicology profiles, and to initiate clinical testing of this new generation of anticancer agents with the ultimate goal of improving treatment options for head and neck cancer patients.
Project 4
The use of nanoparticles for tumor targeting and drug delivery is one of the most exciting and clinically auspicious areas in nanotechnology. The proposed research aims to develop a new class of self-assembled and biodegradable nanoparticles carrying the chemotherapy drug Taxol for the targeted therapy of head and neck cancer. Our research group has shown that over 50% of cancer tissues from head and neck cancer patients express a high level of folate receptor, raising exciting possibilities for the development of novel folate receptor-targeted therapeutics for this patient population. Our team has recently developed a "ternary" nanoparticle structure by linking both a hydrophobic cancer drug (Taxol-TM) and a tumor-targeting ligand [folic acid (FA)] to a hydrophilic and biodegradable polymer [heparin (Hep)], resulting in a tumor-targeted Taxol delivery nanoparticle (Hep-FA-Taxol). We demonstrate 17-fold higher tumor growth inhibition compared to free Taxol in a head and neck tumor xenograft model after systemic delivery of Hep-FA-Taxol nanocomplexes. In this project, we will further develop and characterize this ternary nanoparticle therapeutic drug. We plan to conduct preclinical studies to determine the specificity and efficacy of the Hep-FA-Taxol nanoparticle in head and neck tumor xenograft models. We will then determine biodistribution, toxicology, pharmacokinetic (PK), and pharmacodynamic (PD) in animals. The ultimate goal of this study is to bring this promising tumor targeted Taxol-nanoparticle (Hep-FA-Taxol) to a phase Ib clinical trial. Combined, these studies will test the hypotheses that delivery of Taxol using Hep-FA-Taxol nanoparticles will improve (1) specific distribution of Taxol in tumor lesions expressing a high level of folate receptors, (2) intracellular concentration of Taxol to overcome drug resistance, and (3) therapeutic efficacy for the treatment of head and neck cancer. The proposed research will allow us to conduct preclinical and clinical studies to bring this novel nanotherapeutic drug from bench top to clinical application. The development of this tumor targeted Taxol delivery nanoparticle may provide head and neck cancer patients with an effective treatment while reducing systemic toxicity. Administration Core
The Administration Core of the Emory Head and Neck Cancer SPORE program will be directed by the Principal Investigator, Co-Principal Investigator, and includes the SPORE Executive Committee, Internal Advisory Board, and External Advisory Board. The Administration Core will be responsible for the oversight, coordination, and administration of all Emory University Head and Neck Cancer SPORE Program activities. The core will monitor and facilitate review of research progress, foster new and ongoing research opportunities through distribution of Developmental Research funds, recruit new investigators into the field of translational head and neck cancer research through distribution of Career Development funds, prepare SPORE renewal applications, maintain fiscal oversight of essential SPORE components including Research Projects and Core Resources, and schedule and facilitate SPORE Executive and Advisory meetings. To this end, the Administration Core will work closely with the directors of the Developmental Research and Career Development Programs, the Research Projects, and the other Cores. In addition, the Administration Core will facilitate interactions between the Emory SPORE and other SPORE groups and respond to National Cancer Institute initiatives. The Administration Core is also responsible for assuring effective communication between SPORE components including subcontractors and off-campus collaborators. Through the implementation and administration of Research Projects, Core Resources, a Developmental Research Program and a Career Development program, the Emory Head and Neck Cancer SPORE will provide a superstructure that transcends individual investigators, departments, schools and institutions, enabling an organ-specific research program focused on accelerating the patient benefits of research. Specimen Resources and Pathology Core
The goal of the Specimen Resources and Pathology Core (SPRC) is to provide superior technical expertise to the investigators on this proposal. Experienced head and neck pathologists and cytopathologists will work closely with each SPORE project as well as the Biostatistics and Administrative Cores to ensure efficient and highly-coordinated procurement, archiving, and storage of human tissue samples. Continuous communication between the clinicians, scientists, research nurses, biostatisticians, and pathologists together with established standardized operating procedures for all core activities will provide optimal tissue collection and accurate processing, analysis, and storage of each sample. The SRPC will function as the main repository of patient specimens and will oversee specimen processing and histopathology. This Core will utilize and expand the already well-established tissue banking efforts at Emory University for translational research. Histopathologic analysis by the Core pathologists will confirm the quality and presence of the expected study tissue in research specimens. Selected cellular biomarkers will be explored using immunohistochemistry. These immunostains will be interpreted by core pathologists. Cytology specimens will be generated, and cytopathologic support in processing and interpreting the specimens will be provided. In addition, animal study specimen processing, histopathology, immunohistochemistry, and pathologic interpretive support will be provided. Taken together, the primary objectives of the Specimen Resources and Pathology Core are to:
By assisting the researchers in these translational projects, we hope to advance the understanding of how oral cancer develops and aid in the development of treatment and preventive stategies for oral cancer. Biostatistics and Data Management Core
The purpose of the Biostatistics and Data Management Core for this program SPORE is to provide a comprehensive, multi-disciplinary resource for design of clinical and basic science experiments, development of appropriate and innovative statistical methodology, statistical analysis, and summary of results. The Biostatistics and Data Management Core has the following overall goals: to provide statistical consulting and collaboration on the design, conduct, analysis and interpretation of all SPORE research studies and cores, and to provide, manage and maintain a high-quality research database that supports the research projects and cores while preserving the confidentiality of all subject data. The specific aims are:
Developmental Research Program
The Head & Neck Cancer SPORE supports a Developmental Research Program with the goals of identifying new research opportunities in translational research of head and neck cancer, supporting additional meritorious proposals that might expand into full research projects in the future, and enhancing the research of head and neck cancer by increasing the number of investigators working on head and neck cancer. The specific aims are:
Career Development Program
The goal of the Career Development Program (CDP) in head and neck cancer (HNC) is to recruit, train, and mentor young or established scientists in basic, clinical, and translational research in HNC. The CDP is an essential part of the overall effort of this SPORE. In order to stimulate the next generation of translational researchers, attracting talented individuals from the level of post doctoral fellow to assistant professor and defining research in HNC as a central theme of their career is vital. The CDP will provide financial support and mentorship for achieving the goals stated above, while the SPORE itself will provide a nurturing and stimulating environment for candidates who are groomed as future leaders in translational research in this field. The faculty within the SPORE has an excellent track record in mentoring post doctoral fellows, young scientists, and academically-oriented translational clinicians. Thus, the CDP will focus on these three types of investigators by supporting two post doctoral fellows per year during the five-year grant period. The Emory-Winship Cancer Drug Development and Pharmacogenomics Academy (DDPA) has already funded two young investigators, one of whom has chosen to focus on HNC. We plan to support the recruitment of two additional faculty physicians, including a clinical translational investigator in upper aerodigestive and thoracic malignancies, and a basic scientist during the initial 3 years of the SPORE. The second recruitment phase will involve the development of junior and senior faculty from multiple disciplines, potentially including head and neck surgery and organ preservation. Support for these recruits will come from Emory University and the Georgia Cancer Coalition, as well as the Winship Cancer Institute. These surgically oriented investigators will be recruited and supported in the last 3 years of the SPORE. The SPORE-initiated recruitment of new faculty will consider candidates identified through the existing recruitment process, with special emphasis placed on seeking minority candidates and women. We have already awarded seed packages for research to two young women from Emory's Cancer Drug Discovery Program, and the Cancer Control Program intends to supplement this developmental program. |
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