2024: Dinh | Hernandez | Sodji
2023: Burr | Cosper | Kerr
2022: McCoy/Blitzer; Renewal: Fitzpatrick
2021: Fitzpatrick | Zhao; Renewal: Dinh
2020: Dinh | Wieland; Renewal: Ong
2019: Iyer | Ong; Renewals: Bayliss/Hill | Rogus-Pulia | Witek
2018: Bayliss/Hill | Rogus-Pulia
2017: Baschnagel | Gitter | Morris | Russell | Witek
2024 awards
Huy Dinh, PhD
Assistant Professor
Department of Oncology
Modulating immune signaling to enhance immune checkpoint blockade in head and neck cancers
Abstract
Immunotherapy does not give clinical benefits for about 80% of Head and Neck cancer patients. Neutrophils, the most abundant white blood cell type, play a significant role in how well the treatment works. We found markers of neutrophils associated with treatment responses in pre-clinical mouse models. Specifically, we discovered a new signaling pathway, expressed primarily on neutrophil interactions with other cell types that affect treatment response. Our research aims to understand how modulating this signaling can improve Head and Neck treatment, potentially leading to better patient outcomes.
Reinier Hernandez, PhD
Assistant Professor
Department of Medical Physics
Paula Demetrio de Souza Franca, MD
Resident
Department of Surgery, Otolaryngology-Head & Neck
Imaging Hypoxia in Head and Neck Cancer using innovative CA9-targeting radiopharmaceuticals
Abstract
Despite advancements in cancer treatment, oral squamous cell carcinoma (OSCC) outcomes remain poor. Currently it is mainly treated with surgery, chemotherapy, and radiotherapy (RT). However, this can be challenging is cases of hypoxia, where tumors lack oxygen, as RT is usually less effective, making those tumors harder to treat. Carbonic anhydrase IX (Ca9) is a molecule produced by the cancer cells when they lack oxygen, and it is also linked to cancer growth and spread. Inspired by pioneering research, we propose to use a specially marked compound – a radiolabeled molecule – to study hypoxia in head and neck cancer. We will start by examining Ca9 levels in tissue samples, then test how well the radioactive molecule sticks to tissues. Finally, we will use animal models to identify areas of low oxygen and Ca9 in tumors. This study aims to improve our understanding of how lack of oxygen affects head and neck cancer and may lead to new treatments targeting Ca9.
Quaovi Sodji, MD, PhD
Assistant Professor
Department of Human Oncology
Using Radiation to Enhance the Efficacy of CAR T Cell Therapy Against Head and Neck Cancers
Abstract
Despite considerable advancements in treatments like surgery, radiation therapy, and chemotherapy in recent years, the 5-year survival rate for head and neck squamous cell carcinoma (HNSCC) across all sites remains at 66%. It ranks as the sixth most prevalent cancer worldwide, with 890,000 new cases and 440,000 deaths annually. Moreover, its incidence is projected to surpass 1 million new cases per year by 2030. As such, novel therapeutic approaches are needed against HNSCC.
The immune system has the potential to identify and eliminate tumor cells by recognizing mutation-associated neoantigens through adaptive T cell responses. Consequently, immunotherapy has become a crucial aspect of cancer treatment. However, clinically evident tumors often evade destruction by the immune system. In cases where tumors are immunogenic and recognized by a patient’s adaptive immune system, evasion can occur through interactions between immune checkpoint receptors and their ligands. Immune checkpoint inhibition proves to be an effective treatment for such patients. However, for tumors that are poorly immunogenic, the patient’s immune system may struggle to mount an effective anti-tumor response. In such scenarios, employing chimeric antigen receptor (CAR) T cells could potentially confer anti-tumor immunity.
The mesenchymal epithelial transition (MET) receptor is a receptor tyrosine kinase overexpressed in up to 80% of HNSCC. Subsequent studies demonstrated a correlation between a high MET expression and resistance to current standard therapies and poor overall survival in HNSCC. Thus, we hypothesize that MET may be an effective target for CAR T cell therapy against HNSCC. Our hypothesis will be tested in the following aim:
Develop and characterize “universal” DNP-targeted CAR T cells redirected toward MET expressing HNSCC cells using DNP-labelled antibody against MET.
In addition to MET receptor, there are potential new targets in HNSCC that have yet to be targeted by CAR T cells. To enable us to evaluate MET as a CAR T cell therapy target and to screen in the future new potential CAR T cell targets in a relatively short amount of time, we will first develop and characterize a “universal” DNP-targeted CAR T cell that targets a small molecule 2,4-dinitrophenol (DNP) and that can be redirected toward a specific tumor-associated antigen using DNP-labeled antibody. We will subsequently target MET using a DNP-labelled MET antibody. We will finally evaluate the impact of the MET receptor density on the DNP-targeted CAR T cell activation.
Upon completion of these studies, we will have tested two key important concepts: 1) whether MET receptor is a suitable target for CAR T cell therapy in HNSCC; 2) whether a correlation exists between the level of the MET receptor expression (density) and DNP-targeted CAR T cell activation and cytotoxicity. If successful, we will be poised to evaluate in the future, the targeting of the MET receptor by CAR T cells in combination with radiation and advance this approach to translational preclinical testing, with in vivo models of HNSCC.
2023 awards
Adam Burr, MD, PhD
Assistant Professor (CHS)
Department of Human Oncology
In situ Vaccination through intra-tumoral IL-2 injection, immunomodulatory radiation therapy, and checkpoint inhibition
Abstract
Cutaneous squamous cell carcinoma (cSCC) and mucosal head and neck squamous cell carcinomas (HNSCCs) have both undergone a revolution in the treatment of metastatic disease over the past decade. . However, despite these improvements, over 50% of cSCC and almost 80% of HNSCCs do not respond to these therapies. For these patients, their prognosis is poor and there are few effective second line options. We hope to improve treatment responses for these patients through the development of an in situ vaccine. The concept is to improve a patient’s immune response by immunizing them to their own tumor. We do this by killing tumor cells through radiation therapy to provide antigens or targets for the immune response. We then stoke that immune response through a powerful immune system stimulating molecule called IL-2 and the standard checkpoint inhibitor that patients would receive as standard therapy. The primary endpoint of this trial is to determine how much IL-2 can be delivered safely over 3 months. We will analyze blood samples to determine the effect on the immune response. Our hope is that this will lead to a multi-center study with the eventual goal of translating this treatment to clinics everywhere.
Pippa Cosper, MD, PhD
Assistant Professor
Department of Human Oncology
Utilizing centrosome amplification as an Achilles heel in head and neck cancer
Abstract
Each head and neck cancer is a biologically distinct entity, yet all patients are treated identically with the same dose of chemotherapy and radiation. There is an urgent clinical need to tailor therapy to each patient’s tumor characteristics in order to improve patient outcomes. I am proposing to study how errors in cell division caused by extra centrosomes affect radiation sensitivity. Normal cells have 2 centrosomes during mitosis, with one centrosome at each spindle pole to facilitate cell division into two genetically identical daughter cells. Cancer cells frequently have many extra centrosomes, which can lead to cell division in three or more directions resulting in high levels of chromosome missegregation and cell death. However, some cells can cluster their extra centrosomes to avoid loss of essential chromosomes. We propose to study how centrosome amplification and centrosome clustering affects sensitivity to radiation therapy. We hope to be able to use centrosome amplification as a biomarker that can predict radiation response, potentially allowing for the use of lower doses of radiation, which would decrease side effects in patients. We will also study centrosome clustering inhibitors that promote multipolar division in cells with extra centrosomes as this may be a solution to overcome radiation resistance, which is a significant clinical problem in head and neck cancer.
Sheena Kerr, PhD
Assistant Research Professor
UW Carbone Cancer Center
Spatial profiling of the lymph node metastatic niche in head and neck cancer to guide development of microphysiological systems
Abstract
Several treatment options are available for patients with metastatic head and neck cancer, including radiation or systemic treatments such as chemotherapy or immunotherapy, however, there are no predictive tools to determine which of these therapies would work best for each patient. Microphysiological systems (MPS) are in vitro laboratory models that have the capacity to include the multiple cell types found within the tumor and recreate the structure of the tumor that can be essential to accurately model tumor responses. The small cell numbers needed for the MPS mean that the cells required can be isolated from a single piece of tumor tissue allowing creation of patient-specific MPS that represent that persons tumor. These patient-specific MPS have strong potential as precision medicine tools that could be used to determine the most effective treatment choice or help us understand mechanisms of treatment resistance. In order to create MPS that accurately represent metastatic tumors in the lymph node, we will perform an advanced spatial profiling technique on patient tissue samples that will allow us to understand both the cell types that are present in the metastatic site and the tissue architecture that can be recreated in these MPS. The goal of this proposal will be to design an MPS of the metastatic lymph node, guided by the genomic and spatial data collected in our analyses, that has potential for use in precision medicine applications.
2022 award(s)
Sara McCoy, MD
Assistant Professor
Department of Medicine
Grace Blitzer, MD
Assistant Professor
Department of Human Oncology
Defining the Potential of Minor Salivary Gland-Derived Mesenchymal Stromal Cells to Treat Radiation-Induced Xerostomia in Head and Neck Cancer Patients
Abstract
Radiation to treat head and neck cancer can cause debilitating dryness of the mouth because the salivary glands stop making saliva. This dryness can result in poor quality of life due to dental cavities and trouble with speaking, swallowing, or eating. Mesenchymal stromal cells are cells capable of regenerating tissue. Mesenchymal stromal cells grown from bone marrow and fat tissue seem to improve saliva flow in patients who have dry mouth after radiation when they are injected into patients’ salivary glands. To obtain mesenchymal stromal cells from bone marrow and fat tissue, however, patients must undergo painful and potentially dangerous procedures. We propose to use mesenchymal stromal cells taken from salivary glands to treat radiation-induced dry mouth. The biopsy of the salivary glands is minimally invasive and has no major risks associated with the procedure. This study will provide essential pilot data toward future studies involving salivary gland mesenchymal stromal cells to treat radiation-induced dry mouth in head and neck cancer patients.
2021 awards
Megan Fitzpatrick, MD
Assistant Professor
Department of Pathology and Laboratory Medicine
Transcriptome and protein expression analysis of head and neck versus vulvar HPV-related and independent squamous lesions
Abstract
Immunotherapy is a cancer therapy designed to stimulate the body’s immune system to better recognize and fight cancer. However, not all patients will respond to immunotherapy and some may even experience potentially life-threatening adverse events. We propose to study the expression of a novel biomarker (stress keratin 17) that could help clinicians better predict which patients will respond to immunotherapy. We will use novel molecular technologies to examine the tumors and stress keratin 17 expression in relation to response to immunotherapy. Our study will support further large-scale validation studies of stress keratin 17 across solid tumors treated with immunotherapy.
Award Renewed in 2022
Shuang (George) Zhao, MD, PhD
Assistant Professor
Department of Human Oncology
Pilot Study to Develop a Novel RNA-seq Liquid Biopsy for H&N Cancer
Abstract
Precision medicine harnesses sequencing technology to identify what makes a particular tumor “tick”, and in turn, allows physicians to treat patients with drugs that specifically target their tumor. The hope is to match the right treatment with the right patient at the right time. However, a major challenge in head and neck cancer as well as other cancer types is that a piece of the tumor must be extracted from the patient in order for tests to be run. This is not always easy to do, especially in patients with more advanced cancers where surgery is not a good treatment option. A biopsy specifically to get a tumor sample for testing carries risk for the patient for a complication. At the University of Wisconsin Carbone Cancer Center Circulating Biomarker Core, we have developed a new type of “liquid” biopsy which only requires a tube of blood, from which tumor cells are isolated. This makes it possible to routinely collect samples to create and test new research approaches. In our proposal, we seek to apply our unique technology to patients with head and neck cancer in order to create biomarkers for treatment response and resistance. Successful completion of this proposal will provide the data needed to move our work in to clinical trials and improve our ability to tailor our treatments to each individual patient.
2020 awards
Huy Dinh, PhD
Assistant Professor
Department of Oncology
Defining myeloid landscape of head and neck cancer in humans and preclinical mouse model
Abstract
Immunotherapy has revolutionized cancer treatment for late-staged head and neck (HNC) cancer patients. However, the majority of patients still do not respond, which could be improved by understanding the complexity and diversity of immune cells in the head and neck tumor ecosystem. Myeloid cells are white blood cells that play important pro- and anti-tumoral roles in cancer. In this proposal, we aim to identify the unique myeloid cell types that could only be found in the blood and tumor of cancer patients. The anticipated discovery in humans will be further studied using HNC mouse models to define their biological functions. Those cell types will potentially have clinical impacts such as new targets for immunotherapy or biomarkers to predict cancer progression and therapy response. We will employ multi-disciplinary approaches including cancer biology, immunology and bioinformatics for this project and collaborate with HNC clinicians at UW to translate basic findings to clinical relevance. The project will generate pilot data for federal grant applications to contribute to HNC translational research at UW-Madison.
Award Renewed in 2021
Aaron Wieland, MD
Associate Professor
Department of Surgery
Biospecimen Collection of Patients with Squamous Cell Carcinomas of the Head and Neck (HNSCC) At the Time of Surgical Resection for Patient Specific in vitro modeling of Treatment Response
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common worldwide cancer with more than 550,000 new diagnoses annually. In the United States, an estimated 53,260 new cases of cancer of the oral cavity and pharynx will be diagnosed, and 10,750 people will die from the disease. Despite ongoing research, survival rates for advanced head and neck cancers have remained essentially unchanged for several decades. Radiation and chemotherapy, the non-surgical standard of care, yields overall and progression free survival rates on the order of 50%. Conversely, approximately 50% of patients will manifest cancer recurrence. We lack the ability to accurately predict which patients are most likely to benefit from additional therapies such as immunotherapy, targeted molecular therapies or multiagent chemotherapy. The inability to stratify patients and guide treatment decisions in HNSCC is a major challenge to clinicians in the field and there is an urgent need for improved HNSCC disease models. Here we propose to collect HNSCC biospecimens at the time of surgical resection to aid in the development of HNSCC patient-specific research models and correlate clinical outcomes to the responses seen in HNSCC research models, such as that developed by the Beebe laboratory. The Beebe lab has developed a microscale 3D model that includes not only the tumor cells, but other important cells in the tumor environment such as white blood cells and connective tissue components.
2019 awards
Gopal Iyer, PhD
Assistant Professor
Department of Human Oncology
Modulation of Transcriptional Coregulatory Bromodomain and Extraterminal Proteins in Head and Neck Squamous Cell Carcinoma
Abstract
Transcription co-regulators are often implicated in cancer through dysregulated chromatin dependent transcriptional signaling. This project will also explore mechanisms of oncogene and non-oncogenic addiction driven through modulation of BET proteins which would provide a genetic rationale for treatment of head and neck tumors.
Irene Ong, PhD
Assistant Professor
Department of Biostatistics and Medical Informatics
Translating PARADIGM Differential Pathway Analysis of Head and Neck Cancer Subtypes to Direct Drug Treatment Strategies
Abstract
The overall goal of this proposal is to leverage the substantial progress from my recent collaboration with Drs. Tony Gitter, Paul Ahlquist, Peng Liu, and David Page in the development of a PARADIGM-based computational framework for integrating diverse molecular data from HNC patients to better understand the mechanism and differences in regulation of proteins between different subtypes of HNC, by utilizing it to uncover potential new drug treatment strategies. We will build on this important foundational analysis to achieve selected, high priority goals, and also briefly highlight other examples to illustrate the flexibility and numerous potential uses of our PARADIGM-based analysis tool.
In particular, using our innovative computational tools and existing diverse molecular data, we will:
- identify differentially expressed pathways and drug treatment strategies for HNC subtypes using existing diverse types of molecular data and cell line drug sensitivity data,
- identify probable treatment resistance mechanisms by analyzing diverse molecular data from UW HNC patients, SPORE-derived cell lines and patient-derived xenografts (PDXs) and suggest drug treatment strategies, and
- computationally prioritize drug targets from the results of Aims 1 and 2 for collaborative experimental analysis on cell lines or PDXs.
Award Renewed in 2020
2018 awards
Adam Bayliss, PhD
Assistant Professor
Department of Human Oncology
Patrick Hill, PhD
Assistant Professor
Department of Human Oncology
Integration of Machine Learning into a Virtualized Trial Environment for Head and Neck Radiotherapy
Abstract
Using advances in the computational framework of our treatment planning system and basic elements of machine learning, we will characterize and enhance plan optimality in head and neck (HNC) treatment planning. This is the first time basic computational science in artificial intelligence is being applied to radiation therapy treatment planning in a comprehensive manner, from beam modeling, to plan optimization, to treatment delivery and adaptation. Clinical application will be ensured through development of a comprehensive HNC repository of patient radiotherapy data and working with HNC clinicians to create a simplified but extendable characterization of the diagnostic data, plan elements, and outcomes. The result will provide the necessary framework for testing many clinical hypotheses in a large computational environment and will be robust and extendable to other radiotherapy clinics. We will improve several key areas of HNC treatments via machine learning, including:
- Plan Optimization: Knowledge-based learning algorithms will be applied to existing delivery techniques to provide patient-specific pre-planning optimization objectives. Machine learning will be tested and employed via the artificial intelligence algorithm in development by our vendor collaborators and compared with algorithms we would develop.
- Robustness and Adaptation: Adapted data sets will be analyzed using data regression techniques to search for predictive adaptive elements. We will investigate using machine learning to enhance current abilities to account for patient movement, automatic incorporation of both on-treatment setup imaging (such as cone-beam and megavoltage CT) and diagnostic imaging (such as PET or MR) in conjunction with the optimization criteria affecting plan deliverability and robustness throughout treatment.
- Machine Modeling: We will integrate machine learning techniques into the treatment planning system using commissioning data and continued training on future patient-specific quality assurance measurements to autonomously improve the planning model quality. The advent of advanced automation tools enables the creation of a HNC-specific accelerator and beam model that can accommodate site-specific plans to maximize delivery accuracy.
Award Renewed in 2019
Nicole Rogus-Pulia, PhD
Assistant Professor
Department of Medicine
Effects of Radiation Treatment on Oral Microbiota and Salivary Profiles in Patients with Head and Neck Cancer
Abstract
Radiation therapy (RT) commonly used to treat head and neck cancer (HNC) provides locoregional disease control with the goal of preserving vital functions of critical structures. Unfortunately, healthy tissues are still in the radiation field, leading to toxicities that include salivary dysfunction, mucositis and dysphagia. Malnutrition can result from oral discomfort combined with dysphagia. Dysphagia along with declining oral health also results in chronic aspiration of bacteria-laden saliva, liquid and food contributing to aspiration pneumonia. Oral dysbiosis, or disruption of the complex equilibrium of bacterial species in the oral cavity, occurs following RT and contributes to declines in oral health. Salivary dysfunction (decreased quantity and altered composition) along with dysphagia likely accelerates the development of oral dysbiosis post-RT. Approximately 50 percent of patients with HNC experience recurrence that may necessitate repeat RT, which further exacerbates these effects. While these toxicities have been documented following initial and repeated RT, their associations with oral microbial profile shifts post-RT have not been characterized. The purpose of this study is to determine the effects of radiation treatment (initial and repeated) on oral microbial diversity as it relates to salivary profiles, swallowing function, and quality of life outcomes.
We propose a prospective pre-post design study with two cohorts of patients with HNC recruited from the UW Head and Neck Oncology program. The first cohort will consist of 10 patients with a new diagnosis of HNC and planned initial RT. The other cohort will consist of 10 patients with recurrent HNC enrolled in SPORE Project 2 with a plan to receive external beam RT in combination with radiotherapeutic CLR 131. We will complete baseline and three-month post-treatment assessments for both cohorts. Outcomes will include oral microbial diversity, saliva quantity and composition, swallowing safety and biomechanics, oral health, xerostomia, level of oral intake, and quality of life. We will quantify and compare changes in oral microbial diversity post-RT between the two cohorts. We will examine associations among these outcomes and oral microbial diversity. These pilot data will support a NIH R-series application to assess the impact of these factors on pneumonia risk in patients with HNC receiving RT.
Award Renewed in 2019
2017 awards
Andrew Baschnagel, MD
Assistant Professor
Department of Human Oncology
The fibroblast growth factor receptors as targets for radiosensitization in head and neck squamous cell carcinomas
Abstract
Locally advanced human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is typically treated with chemoradiation therapy. This approach results in a five-year overall survival rate of 30 to 50 percent. Identifying strategies and potential targets that enhance the effect of radiation could improve outcomes. Fibroblast growth factor receptors (FGFR)—a family of four transmembrane receptor tyrosine kinases that play a role in tumor progression and invasion—could be one such target. FGFRs are amplified in up to 17 percent of patients with HNSCC, and FGFR protein is overexpressed in up to 70 percent of HNSCC tumor samples. This overexpression is mainly seen in HPV-negative tumors. Our preliminary studies have shown that inhibiting FGFR leads to an enhanced radiation effect in an HNSCC animal model. This project will use in vitro and in vivo experiments to build on these findings.
Award Renewed in 2018
Anthony Gitter, PhD
Assistant Professor
Department of Biostatistics and Medical Informatics
Mortgridge Institute
Integrative, Multi-dimensional Bioinformatics Analysis of Head and Neck Cancers
Abstract
Head and neck cancer is typically treated with surgery, chemotherapy and/or radiation. But these standard treatments do not fully take into account differences among individual tumors. Understanding these differences could lead to more personalized treatment approaches. Genomic profiling—examining unique mutations within a tumor—has begun to reveal molecular features unique to different types of head and neck cancer. But several challenges must be addressed to realize the potential for meaningful personalized therapies. There is a need for comprehensive, integrative analysis of genetic, epigenetic and other changes in head and neck cancer. There is also a need to analyze interactions among molecules that lead to changes in a cell. In this project, we will develop computational tools to reveal the specific mechanisms that drive individual tumors and larger functional principles and pathway changes across head and neck cancer.
Award Renewed in 2018
Zachary Morris, MD, PhD
Assistant Professor
Department of Human Oncology
Development of syngeneic murine head and neck squamous cell carcinoma tumor models for testing in situ tumor vaccination therapeutic approaches
Abstract
In previous research, we explored a novel approach to increase anti-tumor immune response by combining radiation therapy and tumor-specific antibodies. We observed a cooperative anti-tumor interaction between these two established treatments in mouse models of melanoma and neuroblastoma. By combining a T cell checkpoint inhibitor with these two treatments we were able to elicit a potent “in situ” tumor vaccine response—a robust local reaction that drives a systemic anti-tumor immune response. For the current project, we will develop mouse models that will enable us to study the combined effects of radiation therapy, a tumor-specific antibody and T cell checkpoint blockade to treat head and neck squamous cell carcinoma.
Award Renewed in 2018
John Russell, PhD
Associate Scientist
Department of Surgery
The effects of chemoradiation on the microenvironment of tongue muscles
Abstract
Chemoradiation (CRT) to treat head and neck cancer exposes normal tissues to radiation. This can cause significant side effects, including speech and swallowing difficulties. Very little research has been performed on underlying biological changes within muscles of the head and neck following radiation. Through this project, we hope to quantify how different dose fractionation schedules affect CRT-induced damage to tongue muscles. We also aim to determine the effect of chemoradiation on structural and functional changes in tongue muscles. Understanding the underlying causes for the swallowing abnormalities seen in individuals who have received CRT could enable better treatment.
Matthew Witek, MD
Assistant Professor
Department of Human Oncology
PET-MRI assessment of early tumor response to predict outcomes of HPV-positive oropharynx cancer patients
Abstract
Historically, five-year overall survival of patients with locally advanced head and neck squamous cell carcinomas (HNSCC) has been 25 to 50 percent. This has limited the ability to study treatment side effects. However, patients with human papillomavirus (HPV)-induced oropharyngeal squamous cell carcinomas (OPSCC) have a relatively high overall survival rate (70 to 90 percent at three years). This makes them a favorable group of patients in which to study treatment-related side effects. In this project, we will use positron emission tomography-magnetic resonance imaging (PET-MRI) to monitor primary OPSCC tumor response during treatment following two weeks of chemoradiotherapy. Through this project, we hope to be able to predict outcomes. This could enable radiation dose de-escalation to reduce side effects while maintaining favorable overall response to treatment.