R37CA255330

Improving the Translational Value of Head and Neck Cancer Patient-in-Mouse Models - Project Abstract:

Patient-derived model systems are commonly used to study tumor biology and test novel treatments for head and neck cancer. These models are established using patient tumors sourced from surgical specimens and typically implanted into the subcutaneous tissue of the mouse. There is little data available to support the decisions we make during the initial handling of the tumor samples and, most importantly, how these decisions impact the results of subsequent studies.

Our long-term goal is to improve outcomes for head and neck cancer patients using valid, predictive, and well-characterized model systems. The overall objective of this application is to improve our use of these mammalian model systems by understanding the impact of choices we make when we establish them. By combining innovative approaches to study cancer evolution with rigorous assessment of tumor biology and therapy response, we hope to ultimately improve the relevance of studies using these mammalian models to improve the care of human patients.

Our central hypothesis is that the approach used to establish patient-derived xenografts has a critical impact on their relevance as translational models. To achieve our goals, we propose three aims.

In Aim 1, we will determine the role of heterotopic vs. orthotopic implantation on the biology of the tumor, how patient-derived animal models change with increasing passage in animals, and how these factors impact tumor evolution.

In Aim 2, we will test the concordance of response between patient-derived models and patients by using patient-derived xenografts established as part of an ongoing (and separately funded) window-of-opportunity trial and will assess consistency in response to standard treatments over time.

In Aim 3, we will use an innovative humanized mouse model developed at Wisconsin to assess the evolutionary interplay between the tumor and immune system, understand whether these novel mice replicate the tumor/immune interface seen in human cancers or in syngeneic HNC models, and investigate how well the response to immunotherapy replicates that seen in patients.

In summary, these studies will provide compelling evidence for how to optimize our use of mouse models of human head and neck cancer. Completion of this project will provide robust evidence delineating and refining best practices for the translational use of patient-derived xenograft animal models of head and neck cancer.

University Of Wisconsin System

<P>TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS; (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION; (3) EPIDEMIOLOGY; (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS; (5) IMMUNOLOGY AND VACCINES; (6) FIELD STUDIES AND STATISTICS; (7) CANCER CHEMOPREVENTION AND INTERCEPTION; (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT; (9) ORGAN SITE STUDIES AND CLINICAL TRIALS; (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES; AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES.</P><P>TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER; TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS; AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE.</P><P>TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH.</P><P>TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY; CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY; DNA AND CHROMOSOMAL ABERRATIONS; TUMOR BIOLOGY AND METASTASIS; AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.</P><P>TO REDUCE CANCER RISK, INCIDENCE, MORBIDITY, AND MORTALITY AND ENHANCE QUALITY OF LIFE IN CANCER SURVIVORS THROUGH AN ORDERLY SEQUENCE FROM RESEARCH ON INTERVENTIONS AND THEIR IMPACT IN DEFINED POPULATIONS TO THE BROAD, SYSTEMATIC APPLICATION OF THE RESEARCH RESULTS THROUGH DISSEMINATION AND DIFFUSION STRATEGIES. PRIMARY EMPHASIS IS ON THE INCLUSION OF CANCER PREVENTION AND CONTROL INTERVENTION(S) IN ANY PROPOSED STUDY.</P><P>TO PROVIDE AN ORGANIZATIONAL FOCUS AND STIMULUS FOR THE HIGHEST QUALITY CANCER RESEARCH THAT EFFECTIVELY PROMOTES INTERDISCIPLINARY CANCER RESEARCH AIMED TOWARD THE ULTIMATE GOAL OF REDUCING CANCER INCIDENCE, MORTALITY AND MORBIDITY.&NBSP;</P>

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Madison, Wisconsin 53715 United States

Single Zip Code

Method to Extend Research in Time (MERIT) Award Extension Request (Type 4 eSubmission Clinical Trial Optional) (PAR-25-324)

Amendment Since initial award the End Date has been extended from 06/30/26 to 06/30/28 and the total obligations have increased 578% from $520,953 to $3,531,021.