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Last Updated: 09/10/21

Head and Neck SPORE

University of Wisconsin

Principal Investigator(s):

Paul M. Harari, MD, FASTRO
Paul M. Harari, MD, FASTRO

Principal Investigator Contact Information

Paul M. Harari, MD, FASTRO
Jack Fowler Professor and Chairman
Department of Human Oncology
University of Wisconsin School of Medicine and Public Health
600 Highland Ave K4/336
Madison, WI 53792
Tel: (608) 263-5009
Fax: (608) 262-6256

Overview

The Wisconsin Head and Neck SPORE is designed to promote translational laboratory and clinical research to improve overall outcome for patients with Head and Neck Cancer (HNC). This highly collaborative research links basic scientists with HNC clinicians to advance novel treatment strategies for this complex cancer population. These patients bear a disproportionate burden from their cancers based on the critical anatomic location of the disease where treatment can compromise speech, swallow, and breathing function, in addition to creating significant alterations in physical appearance and capacity for social interaction. Efforts to improve cure rates must be carefully balanced with efforts to reduce treatment morbidity to enable enhanced overall quality of life for patients. The broad objectives of this SPORE are to: 1) Promote multidisciplinary translational research in HNC, 2) Improve overall survival and quality of life for patients with HNC, 3) Develop new animal model systems of HNC to test novel targeted therapy strategies, 4) Develop common resources (such as patient-derived tumor xenografts) to be shared across institutions to promote translational research, and 5) Translate promising new molecules developed at the University of Wisconsin through preclinical and clinical testing. The Wisconsin HN SPORE has designed four primary research projects. Project 1 will define and target molecular pathways that drive HNC using new mouse model systems, and identify biomarkers of prognostic value for clinical investigation. Project 2 will examine a novel, tumor-selective radiolabeled molecule developed at UW that internally targets HN tumors with radiation and shows potential to reduce toxicity from conventional treatment. Project 3 investigates molecular targeting of HNC with novel synstatin peptide therapeutics that disrupt signaling complexes coupled to receptor tyrosine kinases. Project 4 investigates the role of the receptor tyrosine kinase AXL in HNC therapy response and resistance to help design more effective future treatment strategies. The Wisconsin SPORE will support this research with three Cores (Administrative, Pathology and Biostatistics), a Career Enhancement Program and a Developmental Research Program.

The ultimate goal of the Wisconsin Head and Neck SPORE is to advance translational research to improve the outcome for Head and Neck Cancer (HNC) patients. HNC is the sixth most common cancer worldwide with over 600,000 new cases diagnosed annually. In the US alone, there are approximately 56,000 newly diagnosed HNC patients each year. These patients frequently bear a disproportionate burden from their cancers based on the critical anatomic location of the disease. These tumors and their treatment often compromise speech, swallow and breathing function, in addition to creating significant changes in physical appearance and social interactions. Efforts to improve cure rates must be carefully balanced with efforts to reduce treatment morbidity to enable a truly improved overall outcome and future for HNC cancer patients.

Specific Objectives and Goals for the Wisconsin Head and Neck SPORE:

  1. Promote multidisciplinary translational research in HNC.
  2. Improve overall survival and quality of life for patients with HNC.
  3. Develop new animal models that better reflect human HNC and test novel therapy strategies.
  4. Develop common resources (e.g., human patient-derived xenografts) to be shared with other institutions to promote advances in HNC research and treatment outcome.
  5. Translate promising new molecules developed at UW (CLR1404, Synstatins) through preclinical testing in HN tumor models and into human clinical trials.

Project Themes: The four research Projects of the Wisconsin HN SPORE have developed substantial preliminary data over the last several years to support the translational goals of the SPORE. The SPORE brings forward two new molecules developed at Wisconsin (CLR1404 in Project 2, Synstatins in Project 3) for translational testing in HNC. New genetically engineered mouse models (Project 1) and new patient derived xenografts (PDXs) developed at Wisconsin catalyze projects and become valuable resources for developmental research and career development projects, as well as other HN SPOREs and researchers. A highly promising new molecular target in HNC therapy and resistance is investigated (AXL) and two unique phase I clinical trials (Projects 2 and 4) are proposed to advance bench to bedside findings.

Project 1: New HPV+ and HPV- mouse models for HNC will be utilized to define mutations that drive HNC development.
Project 2: A promising new imaging and cancer therapy molecule (CLR1404) developed at UW for the treatment of HNC patients will be advanced and will culminate in a phase I clinical trial of CLR1404 combined with reduced-dose external beam radiation in recurrent HNC patients.
Project 3: Newly developed synstatin peptides will be utilized to target novel mechanisms of EGFR and IGF1R signaling during HNC growth, survival and progression. Biomarkers will be screened to be used as prognostic indicators and to report on synstatin efficacy.
Project 4: The role of the receptor tyrosine kinase AXL in therapeutic resistance to the anti-EGFR antibody cetuximab will be investigated to determine if 1) AXL mediates resistance by activating the HER3/PI3K/Akt axis via Src family kinases, 2) targeting AXL in mouse models of cetuximab resistance enhances tumor response to cetuximab and 3) AXL predicts resistance to cetuximab in HNC patients and targeting AXL in cetuximab-resistant PDXs enhances tumor response to cetuximab therapy.

The cores provide support for the main research projects, developmental research program, and career enhancement program to promote excellence and enhance translational research for the HN SPORE research efforts.

Project 1: Defining and Targeting Pathways that Drive H&N Cancer

Project Co-Leaders:
Paul F. Lambert, PhD (Basic Science Co-Leader)
Timothy McCulloch, MD (Clinical Co-Leader)

Theme: Recent exome studies have defined the mutational profiles of over 100 human HNCs. In those cancers that were not associated with HPVs the number of genes frequently found mutated was substantially higher than in HPV-positive (HPV+) HNCs. Nevertheless, these mutated genes are limited in number making it feasible using a suitable genetically engineered mouse (GEM) models to determine which of these genes are true drivers of HNC. In this project we will make use of our prior expertise in developing mouse models for human cancers to identify mutations that drive both HPV- and HPV+ cancers, identify potential therapeutic targets for treating these cancers, and identify biomarkers that are predictive of disease severity and response to therapy in human HNCs.

The Specific Aims of Project 1 are:

Aim 1. Define mutations that drive head and neck carcinogenesis

Aim 2. Identify therapeutic targets for HPV+ and HPV- HNC

Aim 3. Identify biomarkers that are predictive of disease severity and response to therapy

TRANSLATIONAL RELEVANCE: In this project we make use of our prior expertise in establishing preclinical, mouse models for HNCs to identify driver mutations in these cancers, and evaluate the importance of specific genes as therapeutic targets in treating HPV+ vs HPV- HNC. Genome wide analyses of these mouse models will be used to identify biomarkers that are predictive of disease severity and response to therapy in human HNCs. Using human patient-derived xenografts and well-annotated human HNC tissue microarrays, we will perform human endpoint analyses to identify prognostic biomarkers that predict tumor response of individual HNC patients to the novel clinical treatment strategies being tested in this project.

Project 2: Therapeutic Combination of CLR1404 with External Beam Radiation in H&N Cancer

Project Co-Leaders:
Paul M. Harari, MD, FASTRO (Co-Leader)
Gregory K. Hartig, MD (Co-Leader)

THEME: Approximately 50% of patients with head and neck cancer (HNC) manifest recurrence following initial treatment. Although a proportion of these patients remain potentially curable with further local treatment approaches (surgery, radiation, chemoradiation), retreatment is technically challenging and accompanied by a significant risk of irreversible damage to normal tissues. Surgery is often limited by tumor adherence to critical structures (e.g. base of skull, neurovascular bundles), whereas radiation is often limited by normal tissue tolerance (e.g. spinal cord, bone, cartilage). Thus, there is a compelling need to identify improved treatment approaches for patients with loco-regional HNC recurrence.

In this project, we will test a promising new radiolabeled molecule (CLR1404) developed over the last decade at the University of Wisconsin. CLR1404 provides the opportunity for tumor-specific internal delivery of radiation thereby enabling combination with reduced dose external beam radiation in the treatment of recurrent HNC. This agent shows selective accumulation and retention in human tumors across a broad spectrum of animal models (over 50 to date) including our HNC patient-derived xenografts. CLR1404 is a radiolabeled phospholipid ether analog with powerful potential as an imaging agent (labeled with 124I) and as a therapy agent (labeled with 131I).

The Specific Aims of Project 2 are:

Aim 1. Examine uptake and retention of CLR1404 across a diverse panel of HNC xenografts

Aim 2. Quantify the ability of CLR1404 to augment external beam radiation response in HNC model systems

Aim 3. Perform a phase I clinical trial that combines CLR1404 with reduced-dose external beam radiation in patients with loco-regional recurrence following prior HNC radiation

TRANSLATIONAL RELEVANCE: We will first investigate the capacity of CLR1404 to accumulate and retain in tumors following systemic administration in HNC animal model systems. This will include detailed evaluation of dose deposition in mice harboring human HN tumors xenografts following treatment with radiolabeled CLR1404. Thereafter, we will investigate use of combined CLR1404 and external beam radiation to improve tumor control over that achievable with external beam radiation alone. This will provide experimental proof that radiolabeled CLR1404 augments tumor response to external beam radiotherapy. Finally, we will perform a phase I clinical trial to examine the combination of CLR1404 plus external beam radiation in patients with loco-regional recurrence in previously irradiated HN regions. Clinical endpoints will include feasibility, toxicity, tumor response, CLR1404 tumor uptake and HNC-specific QOL evaluation. Knowledge created by this work will test the approach of combining internal radiation with CLR1404 in HNC retreatment using a unique approach that limits normal tissue toxicities and adverse impact on QOL.

Project 3: Targeting H&N Cancer with Synstatin Therapeutics

Project Co-Leaders:
Alan C. Rapraeger, PhD (Basic Co-Leader)
Justine Bruce, MD (Clinical Co-Leader)

THEME: Two kinases that are overexpressed and are known to have causal roles in HNC - the epidermal growth factor receptor (EGFR) and the insulin-like-1 growth factor receptor (IGF1R) - are captured, along with two classes of integrins, and assembled into signaling complexes via interaction sites in the extracellular domains of syndecans. The integrins that are captured (the av?3 integrin with IGF1R and the a6?4 integrin with EGFR) are also known to be causal in HNC, suggesting that these two signaling complexes have central roles in HNC progression. Competitive peptides have been derived (called synstatins or SSTNs) that mimic the interaction motifs in the syndecan and compete for the assembly and signaling of these complexes. Importantly, our preliminary findings suggest that the SSTNs may be more effective than current standard therapies at disrupting the survival of HN tumors, as well as precancerous lesions - but have no effect on normal epithelial cells and no apparent toxicity in animals. The hypothesis that we will test is that the SSTNs (SSTNIGF1R and SSTNEGFR) block the invasion and survival of human HNC and represent a promising new therapy for this cancer. This novel therapy will be tested directly on both precancerous lesions and tumors arising spontaneously in a mouse model of HNC, and in comparison to cetuximab or in combination therapy with external beam radiation or cisplatin on human tumors grown as PDXs in immunodeficient mice.

The Specific Aims of Project 3 are:

Aim 1. Characterize SSTN inhibition and develop biomarkers of syndecan-coupled EGFR and IGF1R in HNC tumor cells

Aim 2. Analyze efficacy of SSTN peptides in the 4-nitroquinoline-N-oxide (4-NQO) mouse model of HNC

Aim 3. Analyze biomarkers predictive of syndecan-coupled EGFR and IGF1R activity in human tumors and patient-derived HNC xenografts (PDXs) undergoing SSTN therapy

TRANSLATIONAL RELEVANCE: The overall goal of this project is to translate our characterization of newly discovered syndecan-coupled IGF1R and EGFR signaling mechanisms into the design of SSTN peptides and their use as a new therapy for HNC. Our proposal will use human tumors transplanted directly from the patient into immunodeficient mice and grown as xenografts to investigate the efficacy of these promising peptides as a new HNC therapy. We will develop biomarkers to be used as prognostic indicators in screening of human HN tumor specimens from annotated tissue microarrays (TMAs) that reflect distinct HN tumor sites. These focused biomarkers will then report on synstatin efficacy during therapy. Our goal when this work is completed will be to conduct more in-depth toxicology studies in mice and dogs using peptide certified for use in humans as a final step before filing an investigational new drug (IND) with the FDA and proceeding to a phase I clinical trial.

Project 4: Role of receptor tyrosine kinase AXL in HNC therapy resistance

Project Co-Leaders:
Deric L. Wheeler, PhD (Co-Leader)
Randall Kimple, MD, PhD (Co-Leader)

THEME: Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor and is used, in combination with conventional chemotherapeutics and radiation, in the management of HNC. Despite clinical successes, approximately two-thirds of EGFR expressing patients do not respond to cetuximab-based therapy. Further, of patients who initially respond, the vast majority eventually become refractory to cetuximab indicating that intrinsic and acquired resistance to cetuximab is a significant clinical problem in the treatment of HNC. Recent work from our laboratory has identified a novel receptor tyrosine kinase, AXL that plays a direct role in cetuximab resistance. In the current proposal we will focus investigations on 1) the mechanism by which AXL imparts cetuximab resistance, 2) promising new monoclonal antibodies, that target AXL to determine if AXL blockade can re-sensitize cetuximab resistant tumors (patient-derived xenografts), to cetuximab therapy and 3) test the hypothesis in human patients that elevated AXL expression can predict response (biomarker) to cetuximab and thus help guide more precise therapeutic strategies in the treatment of HNC patients.

The Specific Aims of Project 4 are:

Aim 1. Determine A) how AXL activates the HER3/PI3K/Akt pathway in HNSCC and B) if AXL mediated activation of the HER3/PI3K/Akt pathway leads to CTX resistance

Aim 2. Determine if targeting AXL in mouse models of CTXR can enhance and re-sensitize tumors to CTX

Aim 3. Determine A) whether AXL predicts resistance to CTX in HNSCC patients and B) if targeting AXL in CTXR PDXs enhances tumor response to CTX therapy

TRANSLATIONAL RELEVANCE: Preliminary data suggests that HNC patient-derived xenografts that express elevated levels of AXL predict resistance to cetuximab. In this application we will take advantage of a window-of-opportunity clinical trial to assess if high expression of AXL predicts resistance to cetuximab in HNC patients. From this patient data we will then develop patient-derived xenografts directly from patients with known cetuximab resistance. These tumors will be tested to determine if AXL blockade can re-sensitize tumors to cetuximab. Findings stemming from this work have the potential to shift future treatment practice paradigms by increasing our ability to predict those patients most likely to benefit from cetuximab and thereby personalize treatment approaches in advanced HNC.

Administrative Core

Core Directors:
Paul M. Harari, MD, FASTRO
Paul F. Lambert, PhD (Co-Director)

The Administrative Core will provide the operational structure necessary for the planning, implementation and management of all SPORE activities by providing the leadership and organizational supervision required for the efficient, progressive and successful conduct consistent with the program goals and SPORE mission.

The Administrative Core will centrally provide a wide variety of administrative coordination, oversight, and research support services to all leaders, co-leaders, investigators and core directors and offer these services in a centralized manner, to promote efficiency and ensure that all SPORE research and activities are focused, connected, complex scientific objectives are met, and existing cancer center resources are utilized and not duplicated.

The Administrative Core will also provide the oversight, monitoring and auditing required to ensure projects are meeting translational endpoints and reach a human application within five years, consistent with the SPORE mission.

The Specific Aims of the Administrative Core are:

Aim 1. Provide the operational structure necessary for managing and supporting the scientific research activities of SPORE projects, cores and development programs

Aim 2. Provide strategic oversight, monitoring and evaluation of projects, cores, and development programs to ensure scientific connection, collaboration, and translational progression

Aim 3. Provide the oversight, regulatory support, coordination and management for the translation of SPORE research and oversee efforts to assure minority accrual

Aim 4. Ensure compliance with all administrative and programmatic mandates of the grant and assure data quality and compliance with regulatory requirements for clinical research

Aim 5. Facilitate translational research collaboration and oversee research resource sharing

Aim 6. Manage SPORE budget, subcontracts, record keeping and all other fiscal activities of the grant

Biospecimen/Pathology Core

Core Directors:
David T. Yang, MD (Director)
Rong Hu, MD (Co-Director

The Biospecimen/Pathology Core (Path Core) of the HNC SPORE is dedicated to the collection, processing, preservation, characterization, annotation, and distribution of biospecimens to enhance translational research in HNC. The theme of this core is to provide SPORE investigators with a reliable, high-quality, and clinically diverse source of HNC biospecimens that are exhaustively annotated with both clinical information as well as tumor specific bioinformatics. This will be achieved by utilizing innovative biospecimen resources such as HNC patient-derived xenografts derived directly from surgical specimens and creating resources such as a comprehensive integrated HNC Biospecimen Database and tissue microarrays. The mission of the Path Core is to provide the type and quality of services that will enable SPORE investigators to easily initiate their translational aims and generate reliable, clinically significant findings that will impact patient care.

The Specific Aims for the Biospecimen/Pathology Core are:

Aim 1. Collect, process, preserve and distribute HNC biospecimens

Aim 2. Provide and maintain a centralized HNC SPORE biospecimen bioinformatics database

Aim 3. Provide a full range of expert services for biospecimen characterization

Aim 4. Serve and support HNC SPORE investigators and collaborate with other investigators in the HNC research community

Biostatistics and Data Management Core

Core Directors:
Menggang Yu, PhD (Director)
Richard Chappell, PhD (Co-Director)
Michael Newton, PhD (Co-Director)

The objective of the BioStatistics and Data Management Core (Stats Core) of the Wisconsin HN Cancer SPORE is to promote excellence in HN cancer translational research by providing dedicated and outstanding biostatistical consultation and collaborative support to the SPORE projects, Pathology Core, Administrative Core, and other investigators whose projects are supported under the Developmental Research and Career Enhancement Programs. This support and collaboration will include laboratory and clinical-based research, focusing on translation from laboratory studies to clinical studies. With direct-from-patient derived xenografts that more closely reflect the biology of the original human cancer, the SPORE will open a new dimension in translational work. The Stats Core will achieve its objective by supporting investigators and providing statistical and data management expertise, thus enhancing the quality and ensuring the validity of the research undertaken in the SPORE. The Stats Core will provide statistical expertise in all stages of the research: from formulation of research questions through study experimental design, data collection and management, to data analysis, interpretation and dissemination of results through publications.

The Specific Aims of the BioStatistics and Data Management Core are:

Aim 1. Collaborate with the HN SPORE investigators in the design of research studies, in analysis and interpretation of data, and in writing of scientific manuscripts disseminating the HN SPORE results to the scientific community

Aim 2. Ensure the transparency and validity of statistical analysis via rigorous data collection and data management activities which include centralized management and standardization of the variety of data that arise from the HN SPORE projects; confidential and secure data archiving and data sharing; and validation and consistency check of collected data across HN SPORE projects

Aim 3. Conduct, when necessary, methodology research to develop new statistical methods relevant to the individual projects

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.