Awarded DRP Pilots

2021 Awards

Jenny Gumperz, PhD headshot

Jenny Gumperz, PhD

Professor
Department of Medical Microbiology and Immunology
Activation of HNC patient T cells using a novel iNKT-DC conjugate cellular immunotherapy
Abstract

Suppression of antigen-specific T lymphocytes is now recognized as a key factor in cancer. Current immunotherapies focus on either interrupting suppressive pathways (checkpoint inhibition), or on delivering genetically-modified cytolytic effector cells (chimeric antigen receptor or CAR-T cells) to directly kill the cancer cells. The Gumperz lab has discovered an alternative strategy to activate human antigen-specific T cell responses that utilizes stable conjugates (adhered pairs) composed of invariant natural killer T cells (iNKT cells) and monocyte-derived dendritic cells (DCs). The iNKT-DC conjugates have elevated cell surface expression levels of multiple co-stimulatory ligands that are known to potently activate T lymphocytes. In preliminary studies we used a humanized mouse model to show that this therapy promotes T cell-mediated regression of human EBV-driven lymphomas in vivo. Here, we will test whether iNKT-DC conjugates promote the activation of T cells from human papilloma virus (HPV)-positive and -negative HNC cancer patients in vitro, and will use recombinant HPV antigens to investigate their ability to activate antigen-dependent T cells. These studies will provide a critical proof of principle to establish the potential of this novel cellular immunotherapy approach for treating HNC patients.

Beth Weaver, PhD

Beth Weaver, PhD

Professor
Department of Cell and Regenerative Biology
A novel mechanism of radiosensitization by docetaxel in HNC
Abstract

In the United States, approximately 56,000 cases of head and neck cancer are diagnosed every year, many of which are caused by infection with human papillomavirus (HPV). Both HPV-positive and HPV-negative head and neck cancers are typically treated with radiation with or without chemotherapy. Unfortunately, 8-year overall survival is only 71% for HPV-positive and 30% for HPV-negative head and neck cancer patients. Thus, new treatment strategies are necessary. However, treatment can lead to difficulty with speech and swallowing, permanent dry mouth, neck stiffness and pain. Thus, a biomarker to distinguish patients that will respond to lower levels of treatment from those that need more aggressive therapy would provide a substantial benefit. Our evidence suggests that a characteristic of head and neck cancers known as chromosomal instability (CIN) can predict response to radiation. Additionally, our data support the idea that patients with tumors unlikely to completely respond to radiation will benefit from additional treatment with the FDA approved drug docetaxel. Here we will test our ideas about how docetaxel works in head and neck cancer and whether docetaxel does indeed sensitize head and neck cancer cells to radiation through a completely novel mechanism, which could allow us to determine which patients will benefit from this drug. Successful development of a method to identify and sensitize resistant head and neck cancers would substantially improve patient outcomes.

2020 Awards

Christopher Bradfield, PhD, professor of oncology

Christopher Bradfield, PhD

Professor
Department of Oncology
Development of mouse models to study aryl hydrocarbon receptor signaling in head and neck cancer
Abstract

Animal models have played an important role in our understanding of head and neck cancer (HNC) biology. Recent advances in genome editing technologies has allowed us to create more innovative models to study cancer development and progression as well as evaluate potential therapies. The aryl hydrocarbon receptor (AHR) pathway may play a role in HNC. The AHR is a transcription factor that binds a range of compounds, including environmental chemicals. However, recent studies have suggested that AHR has other roles in biology, and altering AHR signaling may be a viable route for HNC therapeutics. We will develop new animal models that can be used to study AHR signaling in HNC. We will first build on the existing lox-stop-lox (LSL)-KrasG12D mouse model by linking a fluorescent marker, tdTomato. This model has a mutation that can be expressed and spontaneously develop tumors. In our model, we will add a fluorescent marker so that we can visually identify cells that have the mutation. We will also create a Cyp1a1-Cre mouse model which expresses Cre recombinase in all cells that express Cyp1a1, a well-established and inducible target of AHR. We will also evaluate which tissues and cell populations Cre recombinase is expressed after AHR induction. We will also evaluate our ability to control how many cells respond to AHR induction. Creation and characterization of these models is a crucial first step in our ability to study the AHR pathway in HNC.

Seungpyo Hong, professor of pharmaceutical sciences

Seungpyo Hong, PhD

Professor
Pharmaceutical Sciences
Bispecific Nanocarriers for Synergistic Effect of Immunochemotherapy
Abstract

Head and neck cancer is the sixth most common cancer. It is estimated that >50,000 Americans will be diagnosed with this disease this year. Although a few treatment options are currently available, it is still very difficult to effectively treat metastatic head and neck cancer. An emerging treatment option is to utilize patients’ own immune systems, known as immunotherapy, which can be synergistically effective when used together with conventional chemodrugs. Furthermore, considering the side effect from therapies that are not specific to cancer cells, a drug delivery system that integrates cancer targeting, immunotherapy, and chemotherapy would be a promising approach to substantially increase the treatment efficacy. We therefore aim to develop a new delivery system that carries both immuno- and chemo-drugs specifically to cancer cells only, to maximize the therapeutic efficacy while minimizing toxic effects. To realize this goal, we will engineer a nanoparticle system that contains targeting agents (peptides that are selective to tumor cells) and drug cargo (agents that boost up the immune system against tumor and a commonly used chemodrug). We will then test this nano-scale system using cancer cells and tumor-bearing mice. Upon completion of this study, we will have engineered a novel nanocarrier that is biologically validated, which will help us to successfully compete for larger federal grants to ultimately translate this technology to help head and neck cancer patients.

Award Renewed in 2021

Weiping Tang, professor of pharmaceutical sciences

Weiping Tang, PhD

Professor
Pharmaceutical Sciences
Development of small molecules that can selectively promote the degradation of STAT3 for the treatment of Head and Neck Cancer
Abstract

We propose to develop novel small molecule drug candidates that can engage the body’s own natural protein disposal system to remove a protein called STAT3, which promotes the growth of head and neck cancer (HNC). Many small molecule ligands have been developed for STAT3. Although these ligands can bind to STAT3, most of them only showed moderate inhibitory activity for the function of STAT3 in cells and preclinical models. Our lab recently developed a platform that can quickly generate small molecule degraders for various oncogenic proteins. These small molecules could selectively bind to the specific oncogenic protein target and promote its degradation in cell’s natural protein disposal system. These small molecule degraders showed potent anticancer activity for various cancer cell lines. We propose to apply this platform to the development of drug candidates that can remove the STAT3 protein for the treatment of HNC. We anticipate that novel STAT3 degraders with potent anticancer activity for HNC will be generated from the pilot study in year-1. We will further optimize the pharmacological properties of these molecules in year-2. These data will be used as the preliminary results for the application of major external grants to advance the preclinical development. If the preclinical data are promising, a clinical trial will be initiated with appropriate partners for the development of novel therapeutics to treat HNC patients.

Award Renewed in 2021

Jamey Weichert, PhD headshot

Jamey Weichert, PhD

Professor
Department of Radiology
Theranostic Use of Gadolinium Based Alkylphosphocholine to Overcome Radioresistance In Head and Neck Cancer
Abstract

Most patients with head and neck cancer (HNC) receive radiation therapy (RT). Although RT is very effective at causing damage to tumor cells by depositing energy (dose), it also can hurt healthy tissue around the tumor. Avoiding normal tissues is even important for HNC patients whose cancer comes back following RT because many of these patients are curable with additional treatment approaches; however, re-treatment is challenging without causing normal tissue damage. The emphasis in radiation oncology to better shape the dose to only the tumor has led to advances in image-guided RT. A way to “light up” the tumor so that it can be “seen” would make RT safer by helping to avoid normal tissue. Following intravenous injection, our tumor-targeting carrier molecule, NM600, can selectively deliver a variety of payloads to tumors in vivo. For example, Gd-NM600 has been shown by MRI to brighten a wide variety of tumors, including HNC, for up to 7 days. Gd-NM600 not only makes tumor margins more visible it also can be used to do real-time tumor tracking with MR IGRT systems, like the ViewRay. In addition, Gd-NM600 may provide a dose boost which may lead to better clinical results. The primary goal of this proposal will be to test whether Gd-NM600 can “light up” HNC using MRI. A secondary goal of this proposal will be to test if the dose boost from Gd-NM600 improves HNC survival. Future work will entail testing in larger animals on the clinical ViewRay system.

2019 Awards

Jacques Galipeau, PhD

Jacques Galipeau, PhD

Professor
Department of Medicine
Intra-salivary gland autotransplantation of marrow mesenchymal stromal cells for treatment of radiation induced xerostomia – FDA IND enabling studies
Abstract

Dry mouth is a significant toxicity for the 80% of head and neck cancer patients treated with radiation therapy. To address the lack of effective therapies for this problem, in this grant we will establish the preliminary data needed to apply for FDA approval to test a cellular therapy (injection of specialized cells called mesenchymal stromal cells or MSCs) to treat radiation-induced xerostomia. We will demonstrate that MSCs from patients treated for head and neck cancer have the ability to expand and produce the factors that are important to improve salivary function, that we can quantitative and qualitative measures of salivary production that will be tracked in a clinical trial, and that by using a mouse model of radiation-induced salivary dysfunction we can identify the specific factors made by MSCs that are critical for improving salivary gland function.

Award Renewed in 2020

Randall Kimple, MD, PhD

Randy Kimple, MD, PhD

Associate Professor
Human Oncology
Comprehensive molecular approach to identifying therapeutic targets predictors of radiation resistance in laryngeal and hypopharyngeal squamous cell carcinoma
Abstract

Over one-third of patients diagnosed with advanced cancers of the larynx and hypopharynx (bottom of the throat) who are treated with a goal of cure, will develop recurrent cancer following treatment. Data from our group suggests that nearly 90% of recurrent cancers come back within the area of the highest radiation dose. This suggests that resistance to radiation therapy may be a very important feature of these cancers. We want to use left-over tissue from patients who have had a biopsy or surgery for their cancer to study why they recur. We will use two methods to look at the expression of genes and the modifications of genetic material in these tissues. First we will compare these patterns between patients whose cancer recurred after treatment and those whose cancer was cured. Second we will compare within individual patients samples taken before and after tumor recurrence.We will use techniques that are common in our lab to confirm the importance of the alterations we discover. It is our ultimate goal to identify new treatments for head and neck cancer patients in order to improve the care of these patients.

Alan McMillan, PhD

Alan McMillan, PhD

Associate Professor
Department of Surgery

Poonam Yadav, PhDPoonam Yadav, PhD

Assistant Professor
Department of Human Oncology
Improved Imaging of Head and Neck Cancer Using 0.35T MRI
Abstract

Radiation is an effective and important part of treatment for many Head and Neck cancer patients. Radiation-related damage to non-tumor tissues results in impaired quality of life for the patient. The development of new techniques and tools that can preserve normal tissue remains important.
MRI offers significantly improved soft tissue imaging and thus better identification of tumor and non-tumor tissues compared to CT. Recent advances have led to development of MR guided radiotherapy with onboard MR scanners, allowing real time imaging during therapy. Head and Neck cancer patients when treated with conventional accelerators, have static plans based on CT scans. These plans do not adjust for organ motion and changes in anatomy due to factors such as treatment related swelling, tumor shrinkage, and other changes that occur during the course of treatment.

We propose to use Viewray (an MR-guided radiotherapy system) and improve the capabilities of the system while studying the motion of various structures during simulated H&N radiotherapy treatment to analyze the effect of radiotherapy treatment on tumors and normal tissue. Furthermore, we propose to use ViewRay imaging investigate when therapy needs to be modified to more effectively kill the tumor and preserve normal tissue. Based on the outcome of this project, we anticipate being able to assess whether ViewRay radiotherapy is feasible and advantageous for H&N cancer patients.

Susan Thibeault, PhD

Susan Thibeault, PhD

Professor
Department of Surgery
Development and Characterization of a Murine Laryngeal Papillomatosis Model
Abstract

Laryngeal papillomatosis (LP) is a disease the throat that can transform to cancer. There is no cure for either disease. There has been little research into this disease because there has not been adequate models for study. Using a recently discovered mouse model that can grow LP we would like to develop a model to study this disease. We believe that if we injure the mouse vocal fold we can a place for this virus to enter the tissue. We will characterize this growth and development. We will also further investigate the potential induction of SCCA in our mouse model with alcohol exposure. This work is foundational in the areas of laryngology, virology and cancer. This proposal will result in a novel preclinical model of LP and SCCA that will facilitate further study of these diseases.

Nathan Welham, PhD

Nathan Welham, PhD

Associate Professor
Department of Surgery
Mass spectrometry-based spatial mapping and characterization of proteins/glycans in laryngeal cancer in situ
Abstract

Laryngeal cancer is the second most common head and neck cancer. Cancer cells produce signature proteins and sugars that hijack normal cell function. Identification of these cancer-specific proteins and sugars is important for early diagnosis and treatment, including the development of novel treatments; however, these molecules can be very challenging to detect with traditional techniques. In this project, we propose using a highly-sensitive detection technology, mass spectrometry imaging, to address this challenge and identify proteins and sugars that are characteristic of laryngeal cancer. This technology has an important advantage over alternative approaches in that it is capable of detecting thousands of molecules simultaneously at their original location within a tissue.

Award Renewed in 2020

Deric Wheeler, PhD

Deric Wheeler, PhD

Associate Professor
Department of Human Oncology
Overcoming Axl Inhibitor Resistance Using a Novel, EGFR-Targeted, Nano-Delivery System
Abstract

The TAM (TYRO-3, AXL, MERTK) family receptor tyrosine kinases (RTKs) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC). AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. Since AXL is highly expressed in aggressive tumor types, cancer patients are currently being enrolled in clinical trials testing AXL inhibitors. In recent studies, we analyzed the effects of AXL inhibition using a small molecule AXL inhibitor, monoclonal antibody therapy, and siRNA in HNSCC preclinical models. Anti-AXL targeting strategies had limited efficacy across these different models which our data suggests could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo. Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies co-targeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies.

In this application we are pursuing three areas of research:

  1. In aim 1 our goal is to screen a battery of recently developed AXL/MERTK dual inhibitors test their ability to overcome single agent targeting of AXL in vitro and in vivo,
  2. Aim 2 is centered on the development of unique nanoparticles that can deliver high concentrations of the AXL/MERTK dual inhibitor to the tumor. We have designed two nanoparticles, both exploiting the epidermal growth factor receptor (EGFR) to home the particle to the tumor. In this aim we will perform retention and bio-distribution analysis using IVIS and MALDI Mass Spectrometry, respectively.
  3. The nanoparticle showing the most promising delivery will move forward to tumor studies using HNSCC PDXs and determine if their ability for better tumor control as compared to standard free drug delivery in Aim 3. Successful pursuit of the investigations outlined has the potential to significantly improve and refine current AXL-centric therapeutic approaches in HNSCC.

2018 Awards

Seungpyo Hong, PhD

Professor
Pharmaceutical Sciences Division
Effective Detection and Monitoring of Circulating Tumor Cells (CTCs) from HNSCC Patients
Abstract

Human papillomavirus (HPV) status is the only biomarker currently used in the care of patients with head and neck squamous cell carcinoma (HNSCC). HPV plays an important prognostic role but currently has limited utility as a predictive biomarker. The lack of biomarkers or assays that can select patients who will benefit from chemotherapy is a significant challenge. To fill this knowledge gap, our groups seek to examine the utility of a novel circulating tumor cell (CTC) capture technology in HNSCC within the setting of two prospective clinical trials. This unique combination will allow us to rapidly determine whether our HNSCC-optimized CTC capture technology can play an important role in early assessment of therapy response and/or therapeutic resistance. Our preliminary data demonstrate that our capture device has significantly improved sensitivity and specificity in CTC capture compared to existing technologies and effectively detects changes in CTC numbers during treatment, which correlates to clinical outcome of the patients. Therefore, we hypothesize that CTC kinetics measured using our CTC device can be utilized to select patients who will benefit from either de-intensified treatment or intensified treatment/induction chemotherapy. Our application has two specific aims. In Aim 1, we will apply multiscale engineering approaches to improve the CTC device with three HNSCC cell-specific antibodies (aEpCAM, aHER-2 and aEGFR) immobilized through nanoscale dendrimers and PEG tethers, along with cell rolling-inducing Eselectin.

The surface will be tested using in vitro cell lines and patients’ blood, which will lead to an optimized design of a novel CTC device with significantly enhanced sensitivity and specificity to HNSCC CTCs. In Aim 2, we will conduct clinical validation studies within the setting of a window-of-opportunity trial planned in two UW Head and Neck SPORE-funded clinical trials. We will correlate kinetic changes in CTC numbers and Ki-67 upon cetuximab treatment. The CTC changes will be also compared to a PET/MRI imaging response in patients undergoing chemoradiation. Upon successful completion, this project will lead to a HNSCC-tailored CTC capture device that shows preliminary evidence of clinical impact in terms of identifying responders to therapy. This will put us in a good position to further pursue federal grants such as R01 and IMAT.

Award Renewed in 2019

Peter Lewis, PhD

Associate Professor
Department of Biomolecular Chemistry
Investigating aberrant Polycomb-mediated gene silencing in head and neck tumors
Abstract

Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are a heterogeneous and clinically challenging group of cancers. Nearly 13 percent of these tumors contain putative driver mutations in genes that are mechanistically linked to the regulation of gene expression through methylation of a specific lysine on the N-terminal tail of histone H3. Specifically, loss-of-function NSD1 mutations and gain-of-function histone H3 genes (H3F3A/B) negatively impact histone H3 methylation at lysine 36 (H3K36 methylation), and these mutually exclusive mutations are usually found in tumors arising from the larynx and oral cavity. Previously, we demonstrated that the Lys-36-Met (K36M) mutation in histone H3 impedes cellular differentiation and promotes sarcomagenesis in a cell-type specific context. We found that loss of H3K36 methylation by the H3 K36M mutation promotes a dysregulated genome-wide gain of H3K27me3, a modification involved in gene silencing by the Polycomb complexes PRC1 and PRC2. These and other data led us to hypothesize that Polycomb-mediated gene repression is aberrantly regulated in HNSCCs driven by NSD1 or HS K36M mutations. We now propose to assess if Polycomb-mediated gene silencing is affected in HNSCCs through genome-wide profiling of gene expression and chromatin structure of HNSCC cell line containing the NSD1 or H3 K36M mutations. Additionally, we intend to assess the dependence of Polycomb in HNSCCs through pharmacological and genetic strategies to interfere with Polycomb complexes. We hope to illuminate the aberrantly regulated molecular mechanisms that underlie NSD1/K36M mutations in order to advance exploration of therapeutic avenues.

Tabassum Kennedy, MD

Tabassum Kennedy, MD

Associate Professor
Department of Radiology

Richard Bruce, MD

Richard Bruce, MD

Associate Professor
Department of Radiology
Integration of Research Imaging Repository with Head and Neck Cancer SPORE REDCap
Abstract

Data management and data searchability are components essential to the efficient execution of research within the Head and Neck Specialized Program of Research Excellence (HN SPORE). We are proposing the implementation of an integration between the HN SPORE’s two primary data management platforms, the REDCap Outcomes Database (REDCap) and the Flywheel Data Management Platform (Flywheel).

Given the relatively recent migration of HN SPORE structured data to REDCap, an opportunity exists to dramatically improve the data access and retrieval capabilities to researchers within the SPORE.

The primary innovation of this project is leveraging IT infrastructure systems to dramatically increase the capabilities, speed, and efficiency of SPORE information generation and management. This project represents a further evolution and extension of the critical infrastructure components. The capabilities of the existing REDCap repository will be increased allowing better visibility into underlying primary research and clinical data.

Award Extended in 2018

Award Renewed in 2019

2017 Awards

David Beebe, PhD

David Beebe, PhD

Professor
Department of Biomedical Engineering
Biomimetic Lymphatic Micromodel for Investigating Head and Neck Cancer Metastasis
Abstract

Up to 60 percent of head and neck cancer patients have nodal metastases at original diagnosis. Nodal metastases—the spread of cancer through the lymph system—can be a precursor to distant metastases, which are typically incurable. Thus, head and neck cancer lymphatic spread is an important factor in determining patient treatment and survival. To improve patient outcomes by reducing lymphatic spread, we need to better understand its underlying biological mechanisms. To that end, we will develop a microscale biomimetic model of the lymphatic system to study head and neck cancer metastasis via the lymphatics. Specifically, we will (1) develop biomimetic lymphatic endothelial vessels and (2) examine interactions between lymphatic vessels and head and neck cancer and system response to radiation and molecular signaling agents. We believe the model will be broadly useful to head and neck cancer researchers across the SPORE.

Award Renewed in 2018

Randal Tibbetts, PhD

Randal Tibbetts, PhD

Professor
Department of Human Oncology
RIF1 splicing and chemoirradiation response in HN cancer
Abstract

Most, if not all, human cancers acquire defects in the DNA repair machinery as part of their evolutionary march toward malignancy. In instances where the molecular defect is known, the compromised DNA repair capacity of cancer cells can be used therapeutically. This project will investigate whether alternative splicing (AS) of the Rap1-interacting factor (RIF1), which plays important roles in DNA repair and replication, influences the chemoirradiation response of head and neck cancer cells. Understanding the functional roles of RIF1 isoforms and their genetic interactions with BRCA1—a protein responsible for repairing DNA—and the mechanisms of RIF1 AS in normal cells and cancer cells will likely inform cytotoxic cancer therapy.

Award Renewed in 2018

Beth Weaver, PhD

Beth Weaver, PhD

Associate Professor
Departments of Oncology and
Cell & Regenerative Biology
Chromosomal instability in head and neck cancer
Abstract

Aneuploidy (an abnormal number of chromosomes) and chromosomal instability (CIN; the recurrent gain and loss of whole chromosomes) are hallmarks of head and neck tumors. Studies involving mouse models have revealed that aneuploidy can promote, suppress or have no effect on tumors. The effect of aneuploidy on tumors is determined by the rate of CIN. Human papillomavirus (HPV)-positive head and neck cancers have substantially better response rates to radiation therapy than do HPV-negative head and neck cancers, though the mechanism for this remains unclear. This study will investigate whether HPV-16—an HPV subtype that causes a subset of head and neck cancers—induces CIN in head and neck cancer. It will provide a potential explanation for the better treatment response of HPV-positive head and neck cancer and test the hypothesis that a preexisting low rate of CIN sensitizes head and neck cancers to radiation.

Award Renewed in 2018