Archived record · Edyssy 2014

Hedgehog Signaling In Head And Neck Cancer Stem Cells, And Its Role In Resistance

Agency

NIHNational Institutes of Health

Principal investigator

Antonio Jimeno

Institution

University of Colorado Denver

Amount listed

$433,933

Period

Aug. 9, 2010 to May 31, 2011

Abstract

DESCRIPTION (provided by applicant): Hedgehog signaling in head and neck cancer stem cells, and its role in resistance to EGFR inhibitors Abstract Epidermal growth factor receptor (EGFR) inhibitors are standard of care in head and neck squamous cell cancer (HNSCC) but the efficacy is low and resistance (primary or acquired) is almost universal. We have generated a unique direct patient tumor model (DPTM) of HNSCC that is optimal to study cancer stem cells (CSC). We have found putative CSC that are enriched in tumors after therapy and are able to generate tumors after sorting and implantation, and that have very intense signaling in the hedgehog pathway that is associated with CSC. Our overarching goal is to identify and characterize CSC and what vulnerabilities they may have. In this research proposal we plan to ascertain the role of CSC and their signaling through hedgehog in resistance to conventional therapies, particularly EGFR inhibitors. First we will identify bona fide CSC, and will knockdown the pathway by genetic means. Then, we will conduct advanced animal studies testing rational combinations of conventional therapy with pharmacological hedgehog inhibition. Finally we will test some of the above observations in samples from HNSCC patients undergoing conventional therapy as validation. The significance of these studies is that they will help us understand the basis of resistance to therapies that are in current use. This project tests both the relevance of hedgehog signaling in CSC and of the hedgehog pathway in HNSCC. If positive, these data will provide the rationale to explore hedgehog inhibitors in HNSCC in clinical trials, adding a new potential avenue for these patients. Both are relevant unmet needs.

PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to characterize the precursor or cancer stem cells that are responsible for treatment failures in head and neck cancer, and identify their susceptibility. We will use a model of head and neck cancer that is derived directly from patient's tumors. Although more cumbersome to work with than other simpler models, these tumors more faithfully represent the different components of a cancer, and thus are more informative. We have found that a particular pathway is involved in allowing those reserve cells to survive treatment, and since we have inhibitors available we plan to test their efficacy alone, and with regular chemotherapy. Because our group is also testing the same drugs in patients, if we make any relevant discovery we will be in a very good position to initiate testing in head and neck cancer patients. We will also seek ways to determine what patients will benefit from these drugs, to individualize caner therapy. Public Health Relevance Statement: Narrative The overarching goal of this project is to characterize the precursor or cancer stem cells that are responsible for treatment failures in head and neck cancer, and identify their susceptibility. We will use a model of head and neck cancer that is derived directly from patient's tumors. Although more cumbersome to work with than other simpler models, these tumors more faithfully represent the different components of a cancer, and thus are more informative. We have found that a particular pathway is involved in allowing those reserve cells to survive treatment, and since we have inhibitors available we plan to test their efficacy alone, and with regular chemotherapy. Because our group is also testing the same drugs in patients, if we make any relevant discovery we will be in a very good position to initiate testing in head and neck cancer patients. We will also seek ways to determine what patients will benefit from these drugs, to individualize caner therapy. Narrative The overarching goal of this project is to characterize the precursor or cancer stem cells that are responsible for treatment failures in head and neck cancer, and identify their susceptibility. We will use a model of head and neck cancer that is derived directly from patient's tumors. Although more cumbersome to work with than other simpler models, these tumors more faithfully represent the different components of a cancer, and thus are more informative. We have found that a particular pathway is involved in allowing those reserve cells to survive treatment, and since we have inhibitors available we plan to test their efficacy alone, and with regular chemotherapy. Because our group is also testing the same drugs in patients, if we make any relevant discovery we will be in a very good position to initiate testing in head and neck cancer patients. We will also seek ways to determine what patients will benefit from these drugs, to individualize caner therapy. 3-Dimensional;abstracting;Address;Animals;base;Breast;Cancer Etiology;Cancer Patient;Cancer stem cell;Cell Count;cell growth;Cell Separation;Cells;Cessation of life;Cetuximab;chemotherapy;Clinical;Clinical Research;Clinical Trials;Colon;Colony-Forming Units Assay;conventional therapy;Data;Development;docetaxel;Enrollment;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelial;Erinaceidae;Genetic;GLI gene;Goals;Head and Neck Cancer;head and neck cancer patient;Head and neck structure;implantation;improved;In Vitro;in vitro Model;in vivo;in vivo Model;inhibitor/antagonist;Location;Maintenance;Malignant neoplasm of brain;Malignant neoplasm of pancreas;Malignant Neoplasms;Malignant Squamous Cell Neoplasm;Mediating;melanoma;Modeling;Molecular;Monitor;Mouse Strains;Neoadjuvant Therapy;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Phenotype;Population;Positioning Attribute;precursor cell;Predisposition;Proliferating;Protocols documentation;public health relevance;receptor;Receptor Inhibition;Research Proposals;research study;Reserve Cell;Resistance;Role;Sampling;Signal Transduction;small hairpin RNA;small molecule;smoothened signaling pathway;Sorting - Cell Movement;Specimen;standard of care;Subgroup;Testing;therapy resistant;Transducers;Translations;Treatment Failure;tumor;Tumor Bank;tumor initiation;tumorigenesis;Tumorigenicity;Uncertainty;Validation;Work

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