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Last Updated: 09/13/21

University of Pittsburgh SPORE in Head and Neck Cancer

University of Pittsburgh

Principal Investigator(s) Contact Information

Robert L. Ferris, MD
Director, UPMC Hillman Cancer Center
Hillman Professor of Oncology
University of Pittsburgh
Eye and Ear Institute
203 Lothrop Street — Suite 500
Pittsburgh, PA 15213
Tel: (412) 647-4654
Fax: (412) 647-2080

Jennifer R. Grandis, MD
Associate Vice Chancellor
University of California, San Francisco
CTSI, Box 0558
550 16th Street, 6th Floor
San Francisco, CA 94158-2549
(415) 514-8084


This SPORE renewal application from the University of Pittsburgh focuses on cancers of the head and neck. Three of the four proposed projects are studying head and neck squamous cell carcinoma (HNSCC), a frequently lethal malignancy with few FDA-indicated drugs available for clinical use. Cetuximab is the only molecular targeting agent approved for HNSCC and the single agent response rate is a disappointing 13% with an absence of predictive biomarkers to guide therapy. Two projects in our SPORE renewal are dedicated to improving HNSCC treatment using either a novel STAT3 decoy oligonucleotide initially developed in the SPORE program, or an immunotherapy strategy building on promising findings from the current funding period. Both of these projects include new basic science co-leaders who are highly accomplished and new to the field of translational HNSCC research. A new HNSCC project will focus on the critical area of chemoprevention. Our HNSCC team collaborates extensively with other SPOREs and head and neck cancer investigators at other institutions with the ultimate goal of vertical translation of the more promising and advanced clinical strategies through the cooperative group mechanism. In this renewal application, we now include a project studying differentiated thyroid cancer (DTC). DTC incidence is rising at the fastest rate of all malignancies in the United States and worldwide. Our new DTC project will use a broad next generation sequencing (NGS)-based approach to improve the sensitivity and specificity of fine needle aspirate (FNA) biopsies with the goal of reducing unnecessary surgeries for indolent disease and identifying individuals with aggressive DTC who need additional therapy. The DTC studies include collaborations with the newly funded Thyroid Cancer SPOREs at Ohio State University/MD Anderson Cancer Center (MDACC) and Memorial Sloan Kettering Cancer Center (MSKCC), as well as a multi-institutional network of translational thyroid cancer investigators. The SPORE has an over-arching goal of improving the prevention and treatment of head and neck cancers. In Project 1, which derives from developmental research program (DRP) funding in the current project period, we seek to develop a chemoprevention strategy against HNSCC tumor development and occurrence of secondary tumors. We will also build on research conducted during the present funding period to evaluate two novel treatment strategies in Projects 2 and 3. In the continuation of Project 2, we will systemically administer a cyclic STAT3 decoy olignonucleotide in a phase I trial and test the ability of microbubbles (MB) to deliver high concentrations of the decoy to the tumor using ultrasound (US) with the long-term goal of combining these strategies to optimize therapeutic effects. In the continuation of Project 3 which investigated the immunotherapeutic effects of cetuximab in a 40 patient window-of-opportunity trial, we will investigate strategies for enhancing immune activation by combining cetuximab with a checkpoint receptor inhibitor to abrogate inhibitory immune signals that appear to reduce cetuximab’s clinical activity. In Project 4, also derived from a funded DRP pilot, we will evaluate a novel NGS platform to identify thyroid nodules that do not require surgery as well as those rare, aggressive DTCs where multimodality therapy is indicated.

Overall, the SPORE has 6 Aims to:

Aim 1. Evaluate a well-tolerated chemoprevention strategy using broccoli seed preparations (BSPs) to reduce the morbidity and mortality of HNSCC recurrence and second primary tumor formation;

Aim 2. Develop a safe and effective STAT3 targeting approach that combines systemic delivery for metastatic disease with enhanced delivery to the tumor using a novel MB/US approach;

Aim 3. Optimize the therapeutic benefits of cetuximab by combining this FDA-approved antibody with the FDA approved immunotherapeutic mAb, ipilimumab, which targets suppressive regulatory T cells (Treg), which appear to limit cetuximab-mediated antitumor activity.

Aim 4. Reduce the morbidity and health care costs of over-treating low-risk thyroid nodules and identify the rare, lethal DTC that requires aggressive therapy using a novel NGS-based strategy;

Aim 5. Utilize our administrative, biospecimen, biostatistics, and informatics resources and expertise to optimize translation of new findings from the SPORE to the national and international cooperative group community with which we are tightly aligned; and

Aim 6. Leverage our SPORE infrastructure, resources, and faculty to promote novel high-quality translational science in the developmental research and career development programs of the SPORE.

Project 1: Chemoprevention of Head & Neck Cancer

Project Co-Leaders:
D. Zandberg, MD
G. Delgoffe, PhD

Patients curatively treated for an initial primary head and neck squamous cell carcinoma (HNSCC) are at high risk for developing second primary tumors (SPTs) and succumbing to these secondary tumors, underscoring the tremendous need for a chemopreventive strategy in this disease. We have shown that broccoli seed preparations promote detoxication of carcinogens common to air pollution and cigarette smoke. Our proposal will integrate preclinical and clinical studies to evaluate broccoli seed preparations and the bioactive metabolite of these preparations, sulforaphane, as tolerable, effective, and affordable agents for the prevention of HNSCC SPTs. Long-term success in the treatment of tobacco-related head and neck squamous cell carcinoma (HNSCC) is hindered by an alarming rate of second primary tumor (SPT) development following curative treatment. Patients with human papillomavirus (HPV)-negative HNSCC develop a SPT of the upper aerodigestive tract at the rate of 3-6% per year and are most likely to succumb to these secondary cancers. Although smoking cessation reduces the occurrence of SPTs, moderation of risk is not observed for 5 years, and is insufficient to return risk to baseline. The availability of a well-tolerated and affordable intervention that prevents SPTs would have a major global impact on mortality and quality of life in patients at risk. Unfortunately, no tolerable and effective chemopreventive agents have been identified for HNSCC. Our broad, long-term goal is the rigorous translational development of a tolerable and effective chemoprevention strategy against HNSCC SPTs. Reduced risk for HNSCC and SPTs is associated with diets rich in the Brassica family of cruciferous vegetables, including broccoli. Broccoli is rich in glucoraphanin, which is metabolized to the key bioactive component sulforaphane (SF). SF induces the expression of the transcription factor NRF2, which leads to upregulation of NRF2 target genes. A number of NRF2 target genes encode cytoprotective enzymes, which act to detoxify environmental carcinogens including benzene, aldehydes and nitrosamines found in tobacco smoke. The relevance of the NRF2 signaling pathway for oral cancer chemoprevention is highlighted by the enhanced susceptibility of mice lacking the Nrf2 gene to oral cancer induced by the carcinogen 4NQO. We are developing broccoli seed preparations (BSPs) as a chemopreventive agent against carcinogen-induced cancers, and have determined the safety, tolerability, and pharmacokinetics of BSPs in humans. We have also shown that SF induces NRF2 and NRF2 target gene expression in normal oral keratinocytes and in HNSCC cell lines. Moreover, we have provided first-time demonstration that transcripts for NRF2 target genes are upregulated in the oral mucosa of healthy volunteers treated with SF-rich BSP. We hypothesize that NRF2 pathway activation in oral epithelium can be induced by administering BSP to patients curatively treated for a first tobacco-related HNSCC, and that the target level of NRF2 pathway activation for chemopreventive efficacy in humans can be determined in a mouse model of carcinogen-induced HNSCC. To test this hypothesis we propose two Specific Aims: 1) To investigate the dose-response relationship between sulforaphane (SF) and chemopreventive efficacy in a mouse model of carcinogen-induced HNSCC, and 2) To systematically assess the clinical chemopreventive potential of BSP administration to patients with tobacco-related HNSCC at high risk for SPT.

Project 2: Optimization of STAT3 Decoy Delivery for Head and Neck Cancer Treatment

Project Co-Leaders:
J. Grandis, MD
F. Villanueva, MD

HNSCC is largely a locoregional disease. STAT3 is an attractive target for cancer therapy, including HNSCCwhere STAT3 activation contributes to treatment resistance. This research builds on a track record ofsuccessful clinical translation to enhance delivery of a novel STAT3 inhibitor to HNSCC tumors and identifybiomarkers that can accurately predict which patients will respond to this approach.Project 2 builds on our preliminary data and cumulative reports in the literature that have identified STAT3 as atarget for therapy in HNSCC. Direct injection of a decoy oligonucleotide selectively targeting Signal Transducerand Activator of Transcription-3 (STAT3) into the HNSCC tumor in a phase 0 clinical trial completed during thecurrent funding period demonstrated decreased expression of STAT3 target genes in the tumor. To overcomethe requirement for repeated local injection, we chemically modified the STAT3 decoy to create a more stable,cyclic formulation that can be delivered intravenously with anti-tumor effects and no evidence of toxicity inmouse models. To maximize selective cyclic STAT3 decoy accumulation in the area with highest tumorburden, we are now investigating the potential of microbubble (MB) encapsulation of the cyclic STAT3 decoy,allowing systemic delivery coupled with tumor directed ultrasound to augment regional delivery of the cyclicSTAT3 decoy. Site-directed ultrasound can be tuned to cause destruction of intravenously injected MBsresulting in release and delivery of the cyclic STAT3 decoy selectively into ultrasound-exposed tumor cells. Todefine predictive biomarkers for STAT3 targeted therapy, we will determine the contribution of loss of functiongenetic alterations of a key negative regulator of STAT3, protein tyrosine phosphatase receptor T (PTPRT),which we recently reported in HNSCC and other cancers. This project will have 3 aims to test the safety andfeasibility of these approaches to STAT3 targeting:

Aim 1: To conduct a phase I clinical trial of intravenous cyclic STAT3 decoy in patients withrecurrent/metastatic HNSCC. We will evaluate the safety of intravenous cyclic STAT3 decoy, establish therecommended phase 2 dose (RP2D), and test the hypothesis that cyclic STAT3 decoy reduces expression ofSTAT3 target genes in paired tumor biopsies.

Aim 2: To develop and optimize a platform for ultrasound-targeted MB-mediated delivery of cyclic STAT3decoy. We will test the hypothesis that MB formulations with maximal cyclic STAT3 decoy loading andoptimized acoustic parameters will cause knockdown of STAT3-regulated genes and cell death using in vitroand in in vivo HNSCC models.

Aim 3: To determine the anti-tumor efficacy of intravenous cyclic STAT3 decoy combined with the US/MBplatform developed in Aim 2 and the role of PTPRT mutation or hypermethylation in mediating responses. Wewill test the hypothesis that combined systemic and local delivery will improve responses, particularly inPTPRT mutant or hypermethylated tumors.

Project 3: Checkpoint Receptor Targeting to Enhance Cetuximab Efficacy Against HNSCC

Project Co-Leaders:
R. Ferris, MD, PhD
D. Vignali, PhD

Despite overexpression of the epidermal growth factor receptor (EGFR) on nearly all head and neck squamous cell carcinomas (HNSCC), the EGFR-specific monoclonal antibody (mAb) cetuximab is effective only in a minority of patients. The modest effects of cetuximab have stimulated interest in determining itsanti-tumor mechanisms and the factors that limit clinical responses, in order to improve its efficacy by combining immunotherapeutic approaches. A growing body of evidence, and our preliminary results, indicate that a tumor antigen (TA)-specific mAb, such as cetuximab, can effectively trigger TA-specific cytotoxic T lymphocyte (CTL) responses. However, these effector CTLs are not fully effective, raising the possibility that inhibitory mechanisms limit the efficacy of cetuximab in the majority of patients. Blockade of these inhibitory mechanisms could restore anti-tumor activity and enhance cetuximab efficacy. However, the inhibitory mechanism(s) that are primarily responsible for limiting cetuximab efficacy remain unknown. A high frequency of peripheral blood T-lymphocytes (PBL) and tumor infiltrating T-lymphocytes (TIL) in multiple solid tumors, including HNSCC, express elevated levels of inhibitory receptors (so-called “checkpoints”), such as cytotoxic T lymphocyte antigen (CTLA-4) and programmed death-1 (PD-1),rendering them unresponsive to antigenic stimulation (exhaustion). Furthermore, CTLA-4+ regulatory T cells (Tregs), a potently suppressive sup-population of CD4+ T cells that produce TGF-β, are often present at increased frequencies and with enhanced suppressive capacity in tumors. Collectively, inhibitory receptors on CTL and Tregs are major barriers to effective anti-tumor T cell responses, which has been demonstrated by striking clinical responses to anti-CTLA-4 and anti-PD-1 antibodies. Our previous studies and preliminary data support a working model in which the generation of TA-specific CD8+ T cells triggered by cetuximab in the non-responder patient population occurs concurrently with increased inhibitory mechanisms (including TGF-β) that reduce the clinical response to cetuximab therapy. This project will take advantage of the availability of biospecimens from two novel UPCI clinical trials, which have either recently completed (UPCI 08-013, testing immune biomarkers in single-agent cetuximab treated patients)) or are ongoing (UPCI 12-084, combining cetuximab with anti-CTLA-4 mAb ipilimumab to inhibit Treg). We will determine whether inhibitory mechanisms are responsible for limiting anti-tumor activity induced in cetuximab-treated HNSCC patients and directly assess the impact of CTLA4+ Tregs in this new, ongoing clinical trial.

Aim 1: Determine the extent to which inhibitory mechanisms are altered in tumors from HNSCC patients, and whether this correlates with CTL activity and clinical responsiveness.

Aim 2: Determine the frequency and phenotype of CTL and Tregs in a phase Ib trial of concurrent cetuximab/RT plus ipilimumab (anti-CTLA-4) in locally advanced HNSCC.

Project 4: Molecular Guided Risk Stratification of Thyroid Nodules and Cancer

Project Co-Leaders:
Y. Nikiforov, MD, PhD
L. Yip, MD
U Duvvuri, MD, PhD

Well-differentiated thyroid cancer (mostly papillary thyroid cancer) is largely an indolent disease. Thyroid surgery may not be necessary in many patients who currently undergo invasive procedures for diagnosis and/or treatment. This research builds on a track record at the University of Pittsburgh of developing, and translating into clinical practice, molecular testing for thyroid disease. At the conclusion of this study, we expect to use molecular testing to accurately predict those patients who can safely avoid thyroid surgery. Project 4 is a new project that addresses the epidemic of thyroid cancer. Well-differentiated thyroid cancer is increasing at an alarming rate. There has been a 3-fold increase in incidence of thyroid cancer in the past 3decades. However, the mortality for these patients has remained very low (estimated to be ~2%). Therefore, performing a thyroidectomy for all patients with that thyroid cancer may not be necessary. This project addresses two major issues relevant to the thyroid cancer detection and management. Firstly, we will use next generation sequencing to develop and validate a molecular test that cans more accurately distinguish between thyroid cancer and benign nodules in patients with needle biopsy results that are indeterminate. This molecular test analyses the expression and/or mutation of 62 individual genes and builds on our previous experience using a smaller panel of genes to diagnose thyroid cancer. In the second Aim, we will evaluate the ability of our molecular testing to differentiate low-risk thyroid cancers from more aggressive (high-risk) thyroid cancers. In order to accomplish this goal, we will first interrogate tissue samples obtained from patients who have undergone surgery for thyroid cancer, and then experience disease recurrence or distant metastases. Simultaneously, we will initiate a clinical trial to observe patients with small thyroid cancers. Patients with small cancers will undergo upfront molecular testing and then will be observed. A molecular profile of high-risk disease will be determined by the tumors from patients who progress during the observation period. This information will then be used to inform the second phase of the trial, which will use the molecular signature to separate patients into high-risk and low-risk disease for surgery or observation, respectively.

Aim 1: To test the hypothesis that the NGS-based panel of mutational markers can reliably diagnose cancer in thyroid nodules. This Aim seeks to develop and validate a novel molecular analytic test that can accurately predict which thyroid nodules are malignant versus benign. We will develop the molecular test at the University of Pittsburgh and then validate the utility of this test in 8 other academic centers.

Aim 2: To test the hypothesis that high-risk and low-risk differentiated thyroid cancers have distinct mutational profiles that can be detected in FNA samples and utilized to guide patient management. This Aim consists of two parts, the first sub-aim seeks to use molecular testing to characterize tissues derived from patients with aggressive disease (experience recurrence of cancer or develop metastases). The second sub-aim extends these data to develop and implement a prospective clinical trial that provides patients with small cancers to have observation instead of surgery. The data from this trial will validate that molecular testing can be used to stratify thyroid cancers into a low-risk subtype.

Administrative Core

Core Directors:
R. Ferris, MD, PhD
J. Grandis, MD
J.T. Johnson, MD

The primary objective of the Administrative Core is to provide scientific leadership and general administration for all SPORE related activities. The Administrative Core is responsible for integrating diverse scientific and clinical disciplines into a truly unified multidisciplinary approach to achieve excellence in translational head and neck cancer research. The Administrative Core, led by Jennifer R. Grandis, MD, Robert L. Ferris, MD, PhD, and Jonas T. Johnson, MD, will continue to oversee the day-to-day operations and coordinate administrative and scientific activities. The addition of Dr. Ferris as Co-Director of the Administrative Core and Co-PI of the SPORE enhances translational research initiatives and oversight. Also, Dr. Ferris facilitates multidisciplinary interactions as a key organizer of the Head and Neck Multidisciplinary Clinic and weekly Tumor Board. Dr. Johnson will continue to provide administrative support as Chairman of Otolaryngology and leadership in tissue procurement. Drs. Grandis, Ferris, and Johnson share the overall responsibility for the direction and management of the Head and Neck Cancer SPORE. Specifically, they coordinate all SPORE projects and cores with an emphasis on maximizing collaborative interactions between participants. These interactions are viewed as essential for maintaining a cohesive and scientifically productive multidisciplinary group of investigators. The Core is responsible for managing all Project, Core and Program resources of the SPORE and ensures compliance with all regulatory requirements. The Core convenes all SPORE meetings including those with the Executive Committee and the Internal and External Scientific Advisory Boards. The Core Co-Directors interact with other SPOREs at the University of Pittsburgh and elsewhere to facilitate inter-SPORE collaborations and expedite the translation of important findings. To maintain an organizational structure that will efficiently promote such interactions and maintain a nurturing institutional environment, the Administrative Core has the following specific aims:

Aim 1. Provide scientific management and oversight of all SPORE activities;

Aim 2. Provide fiscal management and oversight of all SPORE activities;

Aim 3. Serve as liaison between our SPORE and the NCI SPORE Program Office, National Cooperative Groups, International Cooperative Groups, industry, other translational researchers, head and neck cancer patient advocates, and the community;

Aim 4. Organize and lead the SPORE planning process in partnership with the internal and external advisory boards (IAB and EAB); and

Aim 5. Optimize resource allocation to achieve the translational research mission of the SPORE by changing direction when necessary and discontinuing projects that successfully mature to the point of gaining independent extramural support or that do not adequately meet their translational goals, and by substituting new projects as appropriate. The Administrative Core will oversee day-to-day operations, coordinate periodic administrative and scientific reviews, and work closely with the NCI Program Office to fulfill these aims. Core personnel will continue to coordinate SPORE activities with those of the UPCI, the departments and schools whose faculty participatein SPORE projects, with outside collaborating institutions, and with advocacy groups.

Histology/Tissue Core

Core Directors:
R. Seethala, PhD
S. Chiosea, PhD

The Histology/Tissue Core continues to function as a critical resource and provide dedicated support to Head and Neck Cancer SPORE investigators. In order to meet the SPORE objectives of improving detection, treatment, and prevention of head and neck cancer through translational research, it is critical to provide investigators with access to high quality tissue, blood, and nucleic acid specimens in conjunction with coordinating clinical and long-term follow-up data, and access to expert histologic, immunohistologic, and molecular interpretation. The Core assists clinical coordinators with the enrollment of patients in SPORE projects, organizes and obtains informed consent, collects, processes, and triages fresh and frozen tissue and blood specimens, and banks samples to meet future needs. The Core provides histopathologic and immunohistochemical preparations and expert pathologic analysis through collaborative efforts. Under the direction of Drs. Seethala and Chiosea, the Core utilizes existing expertise and facilities in the In-Situ Hybridization and Immunohistochemistry Laboratory in the Department of Pathology (paraffin tissue processing), the Molecular & Genomic Pathology Laboratory of the Department of Pathology (collection of FNA samples, tissue micro dissection, nucleic acid isolation, molecular assays including next-resequencing), and the Tissue Microarray Facility of the Department of Pathology (tissue microarray preparation) in order to maximize collaborative use of already existing institutional resources and to eliminate duplication of efforts in a cost-effective manner. The Core operates as a distinct entity with personnel and resources dedicated to supporting the activities of the Head and Neck Cancer SPORE. Because the Core coordinates clinical data collection and tissue/blood banking activities for all head and neck surgery patients and controls, triage protocols and priority schema have been developed to ensure maximal use of samples and to provide equitable distribution that is customized to be project-specific. The Specific Aims of the Core include:

Aim 1. Facilitate patient enrollment into specific projects, provide informed consent for general tissue and blood banking, and collect and manage all clinical and follow-up data to be used in a HIPPA compliant, delinked manner for current and future SPORE-sponsored projects.

Aim 2. Procure, process, and store biological specimens (tissue, blood, serum, saliva), survey data (lifestyle questionnaire), and clinical data (treatment information) from consented patients to support SPORE projects.

Aim 3. Inventory all specimens and subject information in a browser-based secure relational database that is compatible with current technology incorporating common data elements (in collaboration with Informatics Core 3).

Aim 4. Provide basic and customized (project-specific) biospecimen quality control, pathologic analysis of tissue specimens, and create tissue microarrays specific to tumor site, patient demographic variables and clinical trials. Provide expert immunohistochemical and molecular consultation for design and implementation of translational research projects and biomarker analysis to meet SPORE project objectives.

Aim 5. Develop, maintain, genotype and distribute our unique collection of well characterized UPCI Head and Neck Cancer cell lines and HNSCC PDX models to SPORE investigators and collaborators for research.

Aim 6. Provide support in molecular assay design and development and facilitate transition of assays to the CLIA environment if indicated. Facilitate genotyping of tumor specimens using next-gen sequencing approach to support SPORE projects.

Informatics, Biostatistics, and Bioinformatics Core

Core Directors:
D. Normolle, PhD
S. Roy, MD

The Informatics, Biostatistics and Bioinformatics Core provides specialized data management and analysis services to the clinical, laboratory and translational research projects of the Head and Neck SPORE to ensure that experiments are efficiently designed and data are analyzed using the most appropriate methods. The Informatics component provides long-term, comprehensive management to ensure that analyses are based on complete and accurate data. Contemporary translational oncology research requires the integration of bench and clinical science in multiphase development programs. The bench science data are complex, and data must be analyzed in the clinical and biological contexts of head and neck cancer and capabilities and limitations of the analytic platforms. Core 3, the Informatics, Biostatistics and Bioinformatics Core, manages clinical, questionnaire, pathologic, molecular and genomic data in a comprehensive research database and made accessible via a web portal. The core also provides SPORE investigators with study planning (in vitro, in vivo, in silico, and clinical) and biostatistical and bioinformatic analyses.

Specific Aim 1: Biostatistics and Bioinformatics Provide the projects with efficient, unbiased, appropriately powered designs for in vitro, in vivo, in silico, and clinical studies and integrated biostatistical and bioinformatic analyses by statisticians knowledgeable in the science of head and neck cancer, cancer genomics and contemporary high-throughput analytic platforms.

Specific Aim 2: Informatics Ensure that in vitro, in vivo, in silico, and clinical data developed by the SPORE are centrally archived, that biosamples are appropriately curated and that data and samples released for analysis in a fashion compliant with Federal regulations. Core 3 personnel work closely with SPORE investigators, Cores 1 and 2, and UPCI Clinical Research Services (CRS) to ensure that the requisite laboratory and clinical trial data are available for analysis. Core3 integrates clinical and laboratory data and controls the distribution of samples as determined by the SPORE Executive Committee (see Core 2) via the Organ Specific Database (OSD). A lead statistician is assigned to each SPORE Project, but all Core personnel and the entire UPCI Biostatistics Facility are available for consultation. The biostatisticians perform interim analyses of safety for all SPORE clinical trials, and all Core personnel work with the entire SPORE team in preparing progress reports, abstracts, manuscripts, and presentations. Core 3 provides experimental designs and data analyses to awardees in the Developmental Research Program (DRP) and Career Development Program (CDP). Core 3 archives final data and statistical analysis code for all peer-reviewed papers published with the support of the Head & Neck SPORE.

Developmental Research Program

This program provides seed funds to support innovative, high-impact, translational cancer research projects.

Career Enhancement Program

This program provides seed funding to nurture investigators interested in translational cancer research.