Yale University
University of North Carolina
Principal Investigators
Barbara Burtness, M.D.
Anthony N. Brady Professor of Medicine (Medical Oncology)
Chief Translational Research Officer
Chief, Head and Neck Cancers/Sarcoma
Associate Cancer Center Director
Yale Cancer Center
Yale University School of Medicine
333 Cedar Street
New Haven, CT 06520
203-737-7636
Robert Ferris, M.D., Ph.D.
Lineberger Distinguished Professor
Executive Director, UNC Lineberger Cancer Center
Chief of Oncology Clinical Services, UNC Health System
UNC School of Medicine
UNC Lineberger Building
450 West Drive
Chapel Hill, North Carolina 27599
919-966-3037
Overview
The Yale-UNC Head and Neck Specialized Program of Research Excellence (YNC-HN-SPORE) is a highly translational, multi-disciplinary program focused on overcoming treatment resistance in head and neck squamous cell carcinoma (HNSCC). There are over 13,000 HNSCC deaths in the US annually and current treatments often result in functional impairment, pain, or increased non-cancer mortality, even for patients who are cured. The YNC-HN-SPORE seeks to address the critical barriers to effective treatment with a team of clinical and laboratory investigators from Yale, UNC Lineberger, and Fox Chase Cancer Centers, leveraging complementary strengths in cancer biology, genomics, virology, immunology, radiobiology, pharmacology, structural biology, and bioinformatics.
The three coordinated projects are unified by the overarching goal of overcoming treatment resistance, spanning the full translational continuum from mechanistic discovery to clinical validation. The studies undertaken here will help inform ongoing and future clinical trials in HNSCC. They include (1) Inhibiting PLK1 to overcome resistance to ErbB/HER-targeted therapy, (2) Combining demethylation and reverse transcriptase inhibition to prime HPV+ cancers for immunotherapy, and (3) Targeting LAG3 to enhance anti-PD1 immunotherapy. The second project includes a clinical trial testing addition of lamivudine to a combination of a demethylating agent and PD-1 inhibitor, to better regulate inflammation that results from 5-azacytidine-mediated derepression of endogenous retroelements.
Progress across these SPORE projects will generate new discoveries, models, cell lines, and genomically characterized human tumor samples, accelerating HNSCC translational research within the SPORE network and the broader HNSCC research community. The Administrative, Biospecimen and Pathology, and Bioinformatics and Biostatistics Cores help enable and advance these projects through coordination of institutional resources and expertise. Additionally, a Developmental Research Program and Career Enhancement Program will identify and catalyze new projects as well as providing mentoring and support for a new generation of HNSCC researchers.
Project 1: PLK1 inhibition to address adaptive resistance to HER-targeted therapy in HNSCC
Project Co-Leaders
Barbara Burtness, M.D. (Yale) (Clinical/Translational Co-Leader)
Erica Golemis, Ph.D. (Temple) (Basic Co-Leader)
Specific Aims
Current treatments for head and neck squamous cell carcinoma (HNSCC) can help some patients live longer, but the cancer often progresses. Our early research suggests that pairing two targeted medicines, onvansertib and dacomitinib, may work better than either one alone. Onvansertib blocks a key protein involved in cell cycle progression (called PLK1) that cancer cells rely on to multiply. Dacomitinib blocks several related growth signals on the cell surface (the ERBB/HER family). In this project, we will test how well this two-drug combination stops HNSCC growth and learn exactly how it works. We will study the treatment in several preclinical models, including models that have a functioning human-like immune system. A major goal is to see whether shutting down these cancer growth signals also helps the immune system recognize and attack the tumor. If the results are strong, this work will provide the evidence needed to move this drug combination quickly toward a clinical trial for patients.
Aim 1: Characterize AURKA/PLK1 pathway activity in the context of response and resistance to cetuximab combination treatments, HPV status, and resistance mutations
Aim 2: Test the onvasertib-dacometinib combination in genomically distinct cell line and preclinical models of HNSCC, evaluating efficacy and mechanism
Aim 3: Explore effects of onv-dac on anti-tumor immune response in T cell reporter assays, syngeneic models, and immunocompetent Patient-Derived Xenograft (PDX) preclinical models
Project 2: Combining demethylation and reverse transcriptase inhibition to prime for immune checkpoint suppression in HPV+ oropharyngeal cancer
Project Co-Leaders:
Wendell G. Yarbrough, M.D. (UNC) (Clinical Co-Leader)
Natalia Issaeva, PhD (UNC) (Basic Co-Leader)
Specific Aims
The number of head and neck cancers caused by human papillomavirus (HPV) is rising each year in the United States. Unfortunately, today’s treatments can cause severe, lifelong side effects. This project will test new combinations of already-approved drugs to improve how well immunotherapy works, with the aim of improving both survival and long-term quality of life. HPV-positive head and neck cancers often have many genes “switched off” by a chemical tagging process called DNA methylation. Drugs that reduce methylation can switch some of these genes back on, including genes that help the immune system recognize and attack tumors, leading to more immune cells entering the tumor area. However, removing methylation (demethylation) can also activate virus-like stretches of DNA in our genome called endogenous retroelements, which may contribute to the tumor becoming more immune cell-resistant over time. We propose adding a class of drugs that block retrovirus-like activity (reverse transcriptase inhibitors, RTIs), thereby blocking endogenous retroelement mobilization. We expect this will strengthen beneficial immune signals (such as interferon responses), increase tumor cell damage, and improve cancer cell killing. We will use a range of research models to understand how these drug combinations work and to identify markers of response. Finally, a two-arm clinical trial will test whether the experimental treatment improves tumor reduction before surgery.
Aim 1. Identify mechanisms of toxicity of demethylation and RTI in two subtypes of HPV+ HNSCC
Aim 2. Explore immune responses and efficacy of demethylation/PD-1 inhibitors with or without RTI treatment using a novel immunocompetent preclinical model of HPV+ HNSCC
Aim 3. Determine the effect of demethylation, RTI, and PD-1 blockade in a clinical trial in HPV+ HNSCC
Project 3: Targeting LAG3 to enhance neoadjuvant PD1 immunotherapy in HNSCC
Project Co-Leaders:
Robert L. Ferris, M.D., Ph.D. (UNC) (Applied Co-Leader)
Benjamin Vincent, M.D. (UNC) (Basic Co-Leader)
Specific Aims
Project 3 studies how immune “checkpoint” proteins (PD-1, LAG-3, and CTLA-4) shape immune cell activity in patients with head and neck squamous cell carcinoma (HNSCC). These checkpoints can act like brakes on immune cells, limiting the immune system’s ability to attack cancer. Blocking these brakes has the potential to activate immune cells that recognize tumor cells. Using an ongoing clinical trial in which patients receive treatment before surgery (neoadjuvant therapy), we will evaluate two-drug (“doublet”) checkpoint inhibitor combinations that target these proteins. We will measure how these treatments change the tumor and its surrounding immune environment and look for biomarkers. By identifying signals in tissue and from imaging, we can better predict which patients will respond well. The goal is to use these findings to design improved combination immunotherapy trials for HNSCC.
Aim 1: Determine the frequency, antigen-specificity breadth, and functional phenotype distributions of Tumor Antigen(TA)-specific CD8+ T cells pre- and post-Immune Checkpoint Inhibitor (ICI) doublet therapy in treatment-naive HNSCC.
Aim 2: Determine the extent to which metabolic stress in the tumor microenvironment (TME) imprints resistance to ICI doublet therapy in CD8+ Tumor-Infiltrating Lymphocytes (TILs) of HNSCC patients.
Aim 3: Develop pre-treatment selection biomarker signature to personalize doublet ICI use and on-treatment transcriptomic and radiomic signature of pathologic major response.
Administrative Core
Core Co-Directors:
Barbara Burtness, M.D. (Yale)
Robert Ferris, M.D., Ph.D. (UNC)
Erica Golemis, Ph.D. (Temple)
Specific Aims
The Administrative Core will provide scientific, financial, and administrative oversight for all Yale-UNC Head and Neck SPORE (YNC-HN-SPORE) activities. Core A will be responsible for all project and core resources of the YNC-HN-SPORE and will ensure compliance with all general, governmental, and specific NCI/NIH grant regulations and requirements, including timely communications and consultations with the National Cancer Institute (NCI). The Core will oversee and facilitate interactions with all stakeholders, including the institutions leaders. CORE A will coordinate all necessary meetings to administer the programmatic operation of the SPORE, including meetings of the Executive Committee (EC), Internal Advisory Board (IAB), External Advisory Board (EAB), and YNC-HN-SPORE investigators. Through this series of meetings, the Core assumes responsibility for scientific oversight of the YNC-HN-SPORE and will also oversee the activities of the Developmental Research Program (DRP) and Career Enhancement Program (CEP). These functions will assist the YNC-HN-SPORE leadership in ongoing planning and evaluation of the program to ensure progress towards the accomplishment of the proposed aims and resolve scientific disputes that arise. CORE A will coordinate all human subject research-related activities for compliance with institutional and federal regulatory requirements. In addition, CORE A will have overall fiscal responsibility for the YNC-HN-SPORE to ensure cost-effective and efficient use of resources.
Aim 1: To provide comprehensive scientific and administrative oversight for all aspects of the YNC-HN-SPORE.
Aim 2: To oversee and monitor the basic and translational research priorities of the SPORE proposal.
Aim 3: To provide financial management and fiscal guidance for each YNC-HN-SPORE project and core.
Aim 4: To facilitate and monitor interactions among all institutions.
Aim 5: To interface with the NCI, other SPOREs, institutions.
Aim 6: To coordinate outreach efforts, including internal and external publications, website development, seminars, patient/research advocacy activities, and fundraising programs.
Biospecimens Core
Core Co-Directors:
David Rimm, M.D., Ph.D. (Yale)
Wendell G. Yarbrough, M.D. (UNC)
Specific Aims
The Biospecimen CORE is designed to support all aspects of this SPORE grant that need to use or analyze biospecimens. We have 4 specific aims that are designed to span the needs of the projects and include potential future work, including the DRPs and CEPs.
Aim 1: To collect, store and distribute human biospecimens with complete clinical, pathological, and demographic annotation.
Aim 2: To conduct or assist in the collection, maintenance and distribution of HNSCC cell lines and patient derived xenografts.
Aim 3: To conduct or assist in preparation for genomic analyses of biospecimens.
Aim 4: To conduct or assist in the in situ molecular pathology analyses of biospecimens.
Overall, the Core integrates under a single Governance Board three diverse biorepositories capturing the demographics of participants at Yale (Connecticut), Lineberger Comprehensive Cancer Center (North Carolina) and Fox Chase Cancer Center/Temple University (Philadelphia). This resource will allow SPORE investigators and head and neck researchers to generate translational research proposals to address the clinical unmet needs for patients with head and neck cancer.
Biostatistics and Bioinformatics Core
Core Director:
Hongyu Zhao, Ph.D. (Yale)
Joseph Ibrahim, Ph.D. (UNC)
Specific Aims
The goal of the Bioinformatics and Biostatistics Core (CORE C) is to address the statistical design and data analysis needs of the Yale-UNC Head and Neck SPORE (YNC-HN-SPORE) Projects, Cores, Developmental Research Program (DRP), and the Career Enhancement Program (CEP). To this end, we have assembled a highly interactive team of cancer biostatisticians and bioinformaticians from across participating institutions who will work collaboratively with basic, clinical, and translational researchers to advance research in head and neck cancer. The Core is structured so that project investigators work most closely with the Core members with the relevant expertise, while ensuring that rapid and informal interactions to provide data science input is available on site to all YNC-HN-SPORE investigators.
Aim 1: To provide collaboration and expertise in the design, execution, monitoring and analysis of basic, translational, population, and clinical studies for YNC-HN-SPORE.
Aim 2: To oversee and coordinate the collection, management, and analysis of data. Ensure that data collected on all YNC-HN-SPORE studies are of high quality, are evaluated with bioinformatic and statistical rigor, and are accessible within SPORE-affiliated collaborative groups.
Developmental Research Program
Program Co-Directors:
Barbara Burtness, M.D. (Yale)
Robert Ferris, M.D., Ph.D. (UNC)
Erica Golemis, Ph.D. (Temple)
Specific Aims
The primary goal of the Developmental Research Program (DRP) is to identify and fund innovative pilot projects that possess translational potential to make an impact in the field of head & neck cancer in the areas of risk assessment, early detection, biomarkers for prognosis and therapy prediction, mechanisms of carcinogenesis/tumorigenesis, novel therapeutic targets, development of novel therapeutics, and novel treatment approaches. Investigators of funded developmental research projects are strongly encouraged to collaborate with other investigators within and outside of the YNC-HN-SPORE institutions, including other SPORE communities. The purpose is to provide each funded DRP project with the potential to evolve into independent full SPORE projects or equivalent-scale study proposals.
Aim 1: To identify and recruit innovative proposals for pilot projects with translational potential for HNC.
Aim 2: To support new research opportunities for HNC by funding innovative pilot projects.
Aim 3: To enhance collaborations between YNC-HN-SPORE full research projects and DRP investigators (current and potential), and to promote DRP projects to potential full YNC-HN-SPORE or equivalent-scale projects.
Career Enhancement Program
Program Co-Directors:
Kathryn M. Ferguson, Ph.D. (Yale)
Camille Ragin, Ph.D., MPH (Temple)
Jared Weiss, MD (UNC)
Specific Aims
The goal of the Career Enhancement Program (CEP) is to educate and energize the next generation of investigators committed to translational research in head and neck cancer (HNC). Specifically, this program will promote those who will bring novel strategies to bear in the molecular and immunologic therapy of both HPV-associated and HPV-negative squamous cancers of the head and neck, improving outcomes and reducing the morbidity of treatment. The CEP will help foster interest in HNC in junior investigators as they choose careers, and in established investigators looking to redirect their research programs, thus attracting the best talent to address this critical problem.
Aim 1: Identify, support and mentor promising early career basics and translational investigators.
Aim 2: Enhance the careers of established investigators who have a newly defined interest in pursuing translational research in HNC.
Aim 3: Contribute to the development of a head and neck cancer translational workforce with competence across a range of disciplines.