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Principal Investigator: Randall J. Kimple
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $71,347
Funding agency: National Cancer Institute
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 proposed 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.
Terms: <Address><Affect><Age><Animal Experimental Use><Animal Experimentation><Animal Model><Animal Models and Related Studies><Animal Research><Animals><Anti-EGFR Monoclonal Antibody><Anti-Epidermal Growth Factor Receptor Monoclonal Antibody><Biologic Models><Biological><Biological Models><Biology><Cancer Model><Cancer Treatment><CancerModel><Cancers><Caring><Cetuximab><Clinical><Clinical Trials><DNA seq><DNA sequencing><DNAseq><Data><Decision Making><Epidermoid Carcinoma><Evolution><Funding><Generations><Genetic><Genetic Diversity><Genetic Variation><Goals><HNC patient><HPV positive><HPV(+)><HPV(-) HNSCC><HPV(-) head and neck squamous cell carcinoma><HPV+><HPV- HNSCC><HPV-negative HNSCC><HPV-negative head and neck cancer><HPV-negative head and neck squamous cell carcinoma><Head and Neck Cancer><Head and Neck Carcinoma><Histologic><Histologically><Human><Human Biology><Hypodermis><Immune><Immune infiltrates><Immune mediated therapy><Immune system><Immunes><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunologically Directed Therapy><Immunosuppressed Host><Immunotherapy><Implant><In Situ><In Vitro><Length of Life><Longevity><Malignant Head and Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Methodology><Methods><Mice><Mice Mammals><Model System><Modeling><Modern Man><Molecular><Murine><Mus><Nasal><Nasal Passages Nose><Nose><Operative Procedures><Operative Surgical Procedures><Oral><Organoids><Outcome><PDX model><Pathway interactions><Patient Care><Patient Care Delivery><Patient derived xenograft><Patients><Pharyngeal structure><Pharynx><Planocellular Carcinoma><Primary Neoplasm><Primary Tumor><Research><Research Specimen><Resistance><Respiratory System, Nose, Nasal Passages><Role><Sampling><Scientist><Serial Passage><Signal Pathway><Site><Skin><Source><Specimen><Squamous Carcinoma><Squamous Cell Epithelioma><Squamous Epithelium><Squamous cell carcinoma><Subcutaneous Tissue><Subcutis><Superficial Fascia><Surgical><Surgical Interventions><Surgical Procedure><Tela Subcutanea><Testing><Therapeutic Studies><Therapy Research><Throat><Time><Translating><Tumor Biology><Use Effectiveness><Wisconsin><ages><animal experimentations><anti-cancer therapy><anti-cancer treatment><biologic><cancer microenvironment><cancer therapy><cancer-directed therapy><care for patients><care of patients><caring for patients><cost><effectiveness using><expectation><experience><head and neck cancer patient><head/neck cancer><human disease><human model><human papillomavirus (-) head and neck squamous cell carcinoma><human papillomavirus +><human papillomavirus - head and neck squamous cell carcinoma><human papillomavirus negative head and neck cancer><human papillomavirus negative head and neck squamous cell carcinoma><human papillomavirus positive><human papillomavirus- head and neck squamous cell carcinoma><humanized mice><humanized mouse><immune cell infiltrate><immune competent><immune microenvironment><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunosuppressed patient><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><implantation><improved><improved outcome><innovate><innovation><innovative><malignancy><malignant head and neck tumor><model of animal><model of human><mouse model><murine model><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-HPV HNSCC><non-human papillomavirus head and neck squamous cell carcinoma><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><patient derived xenograft model><patient response><patient specific response><pre-clinical><pre-clinical research><preclinical><preclinical research><presence of HPV><presence of human papillomavirus><prevent><preventing><resistance to therapy><resistant><resistant to therapy><response><response to therapy><response to treatment><responsive patient><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><standard care><standard treatment><subcutaneous><subdermal><subdermal tissue><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic response><therapy resistant><therapy response><translational model><treatment resistance><treatment response><treatment responsiveness><tumor><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions>