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Last Updated: 10/17/18

SPORE in Head and Neck Cancer

Johns Hopkins University

Principal Investigator:
David Sidransky, M.D.

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

David Sidransky, MD
Johns Hopkins University School of Medicine
Otolaryngology – Head and Neck Surgery
1550 Orleans Street
CRB II 5th Floor
Baltimore, MD 21231
Tel: (410) 502-5153
Fax: (410) 614-1411
Email: dsidrans@jhmi.edu

OVERALL ABSTRACT

This application for continuation for the Specialized Program of Research Excellence (SPORE) in Head and Neck Cancer at the Johns Hopkins University School of Medicine supports a highly interactive, multidisciplinary, and intra-institutional program. Five research projects, three cores, a career development and a research developmental program are proposed to carry out our translational research in head and neck cancer. The SPORE has given attention in all projects to the presence and absence of HPV infection as a major determinant of disease biology and behavior. Moreover, there are two main themes that permeate our major projects, one is genomics and biology and the other is immunology. Research Project #1- Augmentation of Immune Response to Head and Neck Squamous Cell Carcinoma via Phosphodiesterase Type 5 Inhibition - Co-Investigators, Ivan Borrello (basic) and Joseph Califano (clinic). Research Project #2 - HNSCC From Cancer Genomics to Personalized Biomarkers. - Co-Investigators, David Sidransky (basic) and Nishant Agrawal (clinic). Research Project #3- Improving EGFR-targeted Immunotherapy of HNSCC by Counteracting TGF-[3-mediated Immune Suppression - Co-Investigators, Christine Chung (clinic) and Atul Bedi (basic). Research Project #4 - HPV Vaccine Therapy- Co-Investigators Sara Pai (clinic) and T.C. Wu (basic) Project #5- Etiologic Heterogeneity in Head and Neck Squamous- Co-Investigators, Gypsyamber D'Souza (basic) and Carole Fakhry (clinic) The cores support the research programs (Core #1 - Pathology/ Tissue Core, Dr. Westra; and Core #2- Administrative/Clinical Core (Dr. Sidransky ), Core #3 - Biostatistics and Bioinformatics Core (Dr. Rosner) The Career Development Program(Dr. Sidransky) aids the emergence of new investigators and the Research Developmental Program (Dr. David Sidransky) provides rapid funding of innovative directions.

PROJECT 1: Augmentation of Immune Response to Head & Neck SQUAMOUS CELL Carcinoma via Phosphodiesterase Type 5 Inhibition

Project Co-Leaders:
Ivan Borrello, M.D. (basic)
Joseph Califano, M.D. (clinical)

Head and neck squamous cell carcinoma (HNSCC) is a lethal solid malignancy with 5 year survival estimates of approximately 50%, and is associated with a high rate of systemic immune impairment as well a evasion of a tumor specific immune response. Preclinical and clinical data have shown that PDES inhibitors (tadalafil) can be used to augment immune function in HNSCC patients through inhibition of the cancer-induced myeloid derived suppressor cells (MDSCs). Separate, independent clinical trials in HNSCC patients have shown that tadalafi11) can be safely administered; 2) reduces MDSCs function and numbers; 3) increases global systemic immunity; 4) increases Tlls; and 5) is associated with an increase in tumor-specific immunity. Based on these data we hypothesize that PDES inhibitors may be employed to 1) inhibit cancer induced MDSCs and 2) can increase tumor-specific immune response when combined with conventional multi-modality therapies for advanced head and neck squamous cell carcinoma (HNSCC). To test this hypothesis, we will administer long acting PDES inhibitors concurrently to HNSCC patients undergoing primary radiation therapy +/-chemotherapy, continuously during and after completion of therapy. We will assess 1) MDSC number and function, 2) immune response to vaccine, and 3) tumor-specific immunity at timepoints before, during, and after therapy to determine optimum timing and design of PDES immunotherapy in conjunction with conventional therapy for HNSCC. The long term goal of this project is to investigate and develop PDES inhibitors as safe, well tolerated immune modulators that improve tumor specific immune response in combination with conventional therapy. This approach may also be further developed as a potential adjunct to other immune based therapies, including vaccine based approaches in HPV positive HNSCC (Project 4) and novel combination antibody based therapies (Project 3).

PROJECT 2: HNSCC FROM CANCER GENOMICS TO PERSONALIZED BIOMARKERS

Project Co-Leaders:
David Sidransky, M.D. (basic)
Nishant Agrawal, M.D. (clinical)

Co-Investigators:
Kenneth Kinzler, M.D.
Wayne Koch, M.D.
Victor Velculescu, M.D

More than half a million new cases of head and neck squamous cell carcinoma (HNSCC} will occur in 2011, including 50,000 cases in the United States, making it the sixth most common cancer in the world. These cancers are frequently lethal, with a five-year survival of only -50%. Our group found that HNSCC is characterized by tumor suppressor gene predominance. This distinction is critical because the new generation of molecularly-targeted therapies is directed toward activated oncogenes but such drugs cannot directly target mutated tumor suppressor genes because they are already inactivated. Given the lack of targeted therapies that are available for HNSCC, early detection, monitoring, and surveillance will be critical to decrease the morbidity and mortality associated with HNSCC. The ultimate goal of this proposal is to develop clinically useful biomarkers that can be used for early detection, monitoring, surveillance, and prognosis. To achieve this goal, we propose a detailed genetic analysis of HNSCC (AIM #1}. These genetic changes will be used to develop and validate circulating tumor DNA based biomarker assay in HNSCC (Aim #2). The biomarkers will be correlated with clinical findings and outcomes in a prospective study (Aim #3}. The above studies will identify genetic changes in HNSCC and allow the development of clinically useful biomarkers.

PROJECT 3: IMPROVING EPIDERMAL GROWTH FACTOR RECEPTOR-TARGETED THERAPY OF HNSCC BY INHIBITION OF TRANSFORMING GROWTH FACTOR-Β

Project Co-Leaders:
Atul Bedi, M.D. (basic)
Christine Chung, M.D. (clinical)

The epidermal growth factor receptor (EGFR) is an important target for the treatment of head and neck squamous cell carcinoma (HNSCC). Clinical strategies to target EGFR have focused on monoclonal antibodies (mAbs), such as cetuximab. Cetuximab executes its antitumor effect in vivo via blockade of receptor-ligand interactions and engagement of Fcgamma receptors on immune effector cells which trigger antibody-dependent cell-mediated cytotoxicity (ADCC). Our preliminary studies demonstrate that tumor cell-autonomous expression of TGF-beta is a key molecular determinant of the de novo or acquired resistance of cancers to EGFR-targeted mAb, and provide a rationale for enhancing the antitumor efficacy of anti-EGFR mAb by combinatorial- or bi-functional antibody-based strategies to simultaneously counteract TGF-beta in the tumor microenvironment. The aims of the project are designed to advance the clinical translation of this strategy for treatment of HNSCC; Specific Aim 1: Determine whether tumor cell-autonomous expression of TGF-beta inhibits cetuximab-induced ADCC in patients with HNSCC. Specific Aim II: Determine the in vivo antitumor efficacy and toxicity of dual blockade of EGFR and TGF-beta using HNSCC patient-derived tumor xenografts in mice. Specific Aim Ill: Determine the clinical relevance of TGF-beta as a molecular determinant of resistance to cetuximab in patients with HNSCC, and evaluate the clinical safety of a novel bi-functional anti-EGFR antibody that can sequester and block TGF-beta in the tumor microenvironment. This project addresses the urgent need for effective tumor-targeted therapeutic strategies against HNSCC by: (1) Establishing the role of tumor cell-autonomous expression of TGF-beta as a key mechanism and clinical biomarker of resistance to cetuximab in patients with HNSCC; (2) Improving the treatment of patients with HNSCC and other cancers via novelcombinatorial- or bi-functional antibody-based strategies that simultaneously target and counteract EGFR and TGF-beta in the tumor microenvironment. The project will leverage the expertise and resources of the JHU Tissue Core, Biostatistics Core, and will interact with Projects 1 and 4 of the SPORE-Head and Neck Cancer.

PROJECT 4: HPV VACCINE AND CORRELATES OF RESPONSE

Project Co-Leaders:
Sara Pai, M.D. (clinical)
T.C.Wu, M.D., Ph.D. (basic)

A growing subset of head and neck cancers are caused by infection with the human papillomavirus (HPV) type-16. There is a strong need to develop novel treatment strategies which take advantage of the unique tumor biology of this patient cohort. HPV-specific vaccines represent such a promising, targeted adjuvant treatment option. We plan to evaluate a DNA vaccine, pNGVL4a-CRT/E7 (detox) DNA, in combination with various strategies that can further enhance its potency. In addition to evaluating the safety of the novel DNA vaccine, we plan to measure immunologic responses and characterize tumor infiltrating immune cells within pathologic specimens which will be obtained before and after DNA vaccination as part of routine standard of care. This will give us an opportunity to better understand how this environment may change after vaccination, which will be critical to successful immunotherapy translation. The results of this phase I clinical trial will facilitate a subsequent phase II clinical trial which will evaluate the efficacy of the vaccine in generating HPV-specific CDS+ T cell immune responses which can potentially impact the survival in this patient population by providing long-term immune protection against the development of locoregional recurrence and/or micrometastatic disease. The strengths of our application include the availability of GMP grade reagents developed by the research team and NCI RAID, and previous experience in DNA vaccine clinical trial design and execution with an infrastructure in place at our institution which facilitates further investigation into this area. In addition, we have support from the institution to conduct this clinical trial and access to supportive collaborators who are also evaluating human immune responses elicited after vaccination. The project challenges existing paradigms by coupling chemoradiation treatment with immunotherapy in order to achieve a more potent immunologic response. The results gained from this study will advance the field of immunotherapy by providing information which will allow us to re-evaluate our current strategies to enhance vaccine potency.

PROJECT 5: ETIOLOGIC HETEROGENEITY IN HEAD AND NECK SQUAMOUS CELL CARCINOMA

Project Co-Leaders:
Gypsyamber D’Souza, Ph.D., M.S., M.P.H. (basic)
Carole Fakhry, M.D., M.P.H. (clinical)

Co-Investigators:
William Westra, Ph.D.
Ray Viscidi, M.D.
Patti Gravitt, Ph.D.

The proposed project is a case-control study designed to investigate the role of site, gender and race in human papillomavirus (HPV) -positive head and neck squamous cell cancer (HNSCC). HPV is an established etiologic agent in a subset of HNSCCs which largely ariSe from the oropharynx and is an independent marker of improved prognosis. It appears to be responsible for a shifting epidemiology: oropharyngeal cancer is rapidly rising and is projected to overtake cervical cancer. Men and Whites bear the disproportionate burden of HPV-positive HNSCCs. Reasons for this unique demographic distribution are poorly understood. Given the strong associations of HPV-HNSCC with sexual behaviors, we will explore if gender- and race- related differences in behaviors (sexual, tobacco and alcohol) may in part be responsible for these demographic patterns. We will also investigate whether gender- and racial- differences in immunologic response are driving these distinct demographic patterns. In addition, it is presently unknown how often HPV causes malignancy in non-oropharyngeal squamous cell cancers, despite the potential therapeutic implications.

Therefore, the aims of this proposal are to 1) explore the relative etiologic roles of tumor HPV, tobacco, alcohol and drug use, on odds of non-oropharyngeal site head and neck squamous cell cancer, 2) determine gender differences in risk factors for HPV-HNSCC compared to age, gender, and race matched non-cancer controls and 3) evaluate differences in risk factors for oropharyngeal cancer in black and white patients compared to age, gender, and race matched non-cancer controls.

CORE A: ADMINISTRATIVE CORE

Core Director:
David Sidransky, M.D.

Core Co-Directors:
Joseph Califano, M.D.
Arlene Forastiere

The Administrative Core provides oversight of all SPORE activities including the Projects, Cores, Developmental Research Program, and Career Development Program as it ensures compliance with all local, federal and NCI regulations and requirements. The Core is responsible for communication and consultation with NCI personnel in preparation of all required reports and publications, and has full responsibility for all fiscal and budgetary functions. The Administrative Core has organized all meetings, including the monthly SPORE investigators meeting, meetings with the Steering Committee as well as the Internal and External Scientific Advisory Boards. The Core monitors and actively supports the recruitment of women and minorities, both as participants on SPORE trials, and also as SPORE investigators. It also coordinates travel of SPORE investigators to the annual NCI-sponsored SPORE meeting as well as to the annual Head and Neck SPORE meeting. The Developmental Research Program and the Career Development Program are headquartered here to ensure smooth functioning of these SPORE components. The Administrative Core coordinates activities with the Cancer Center to avoid redundancy and to ensure that joint activities between the Upper Aerodigestive Tract (UAD) program in the Cancer Center and the Head and Neck Cancer SPORE are carried out efficiently and that the programs are complementary and synergistic. The Administrative Core interacts 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 has also facilitated collaborations with various other SPOREs, including the Lung Cancer SPORE at Hopkins and Head and Neck Cancer SPORE programs funded at other institutions.

CORE B: BIOSTATISTICS AND BIOINFORMATICS CORE

Core Director:
Gary Rosner, Sc.D.

Core Co-Directors:
Michael Ochs, Ph.D.
Hao Wang, Ph.D.

The Biostatistics and Bioinformatics Core resource will provide comprehensive biostatistics and bioinformatics consultation and collaboration to all projects in the proposed Johns Hopkins Head and Neck SPORE. In addition, it will provide support for data storage, informatics, and computing, and assist with the identification and solution of complex data tasks arising in the course of project activities. Core members will work with project investigators across a wide spectrum of activities, encompassing data acquisition (including study design, feasibility of objectives, availability of public-access genomic information, and data storage), statistical quality control (including artifact detection and preprocessing of data from genomic technologies), data analysis (including visualization, biostatistical modeling, and assistance with manuscript writing), and development of innovative customized biostatistics and bioinformatics methodologies and tools if required by specific projects. The proposed Head and Neck SPORE Biostatistics Core will be housed in the Division of Oncology Biostatistics/Bioinformatics of the Department of Oncology, an active and committed group of the biostatistics and bioinformatics faculty members, with access to state-of-the-art equipment and a broad range of expertise. This Core resource is the continuation of an existing resource within the original and current Head and Neck SPORE program at Johns Hopkins. Core members have a strong commitment to this SPORE, stemming from (i) a history of collaboration with the investigators of this as well as other SPORE projects, (ii) an active and independently funded agenda of synergistic projects, and (iii) a demonstrated interest and understanding of both the biological and analytical questions and challenges. All proposed projects are anticipated to make use of this resource in every aim.

CORE C: CAREER DEVELOPLMENT CORE

Co-Investigator:
David Sidransky, M.D.

A Career Development program (CDP) is proposed that describes how promising candidates for independent careers in translational cancer research are selected in our SPORE program. We describe the process of how applicants are recruited, retained, and evaluated. We highlight briefly the reasons for selecting past and current awardees as well as their research activities and publications. We update the current career path, publications, and awards of our recipients as well as promotions, grants, and current status of individuals who have been supported by the CDP. The proposed plan for the CDP includes the promotion of outstanding career development projects to full projects within the SPORE and the continued support and integration of successful awardees as project co-leaders, including Dr Borrello, Dr Agrawal, and Dr Chung in the current proposal. The CDP is an integral part of our SPORE and the launching pad for our most successful investigators over the past 10 years.

CORE D: DEVELOPMENTAL PROJECT CORE

Co-Investigator:
David Sidransky, M.D.

A Developmental Research Program (DRP) is proposed for this Head and Neck SPORE to attract new ideas and pilot studies within and outside of our institution. The process for advertising pilot funds, evaluation and periodic review and funding of a spectrum of pilot projects is described. There is a focused abstract describing the proposed pilots as well as subsequent progress and publications from the work once it has been carried out. Promoting pilot projects with translational research potential to full projects within the SPORE is a key area of focus and investment for us. As presented here, several pilots were promoted to full research projects and have become the basis of 3 of the 5 new projects in this cycle. We provide information on outcome of these pilots including success in the competition for outside funds. Collaborations between projects and other SPOREs is also described.

CORE E: TISSUE CORE

Core Director:
William Westra, M.D.

Core Co-Director:
Bishop Justin, M.D.

A concerted effort to collect and bank tissues and biologic fluids from the upper respiratory tract has been an ongoing effort since 1990 under the direction of the Pathology Core leader. Initially, specimen collection primarily targeted overtly malignant carcinomas. Over time, the focus of specimen collection has shifted to tissues and biologic fluids representing much earlier stages along the tumor progression pathway and specimens from control patients without head and neck cancer. The availability of these tissues and cells has contributed to the work of many of the investigators participating in the SPORE, resulting in significant discoveries with high translational impact and numerous peer-reviewed publications. The Pathology Core will continue to: 1) collect, store, process and distribute tissues and biologic fluids for translational research without compromise of patient care; 2) provide well-characterized tumors with respect to site of origin, World Health Organization histologic subtype, differentiation, and fraction of neoplastic and stromal tissues; 3) provide normal control tissue in addition to neoplasms; 4) process and store tissues to address the requirements of all SPORE investigators; 5) include neoplasms with a wide range of biologic potential (e.g. normal, dysplasia, carcinoma sequence); 6) perpetuate tumor growth and expand tumor availability by xenografting tumors into immunodeficient mice; 7) collect blood and exfoliated cells (e.g. oral rinses/oral brushes) from pertinent patients for the SPORE projects; 8) provide the specimens in a timely fashion; and 9) provide well-defined mechanisms for prioritization of the distribution of requested resources to investigators within and external to the Johns Hopkins SPORE.