Diffuse Glioma Heterogeneity and Its Therapeutic Implications

Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have revealed that a remarkable level of genetic, epigenetic, and environmental heterogeneity exists within each individual glioma. Tog...

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Bibliographic Details
Published inCancer discovery Vol. 11; no. 3; pp. 575 - 590
Main Authors Nicholson, James G., Fine, Howard A.
Format Journal Article
LanguageEnglish
Published United States 01.03.2021
Subjects
Animals
Biological Variation, Population
Biomarkers, Tumor
Clinical Decision-Making
Combined Modality Therapy
Disease Management
Disease Susceptibility
Drug Resistance, Neoplasm
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Glioma - diagnosis
Glioma - etiology
Glioma - therapy
Humans
Neoplasm Grading
Neoplasm Staging
Prognosis
Treatment Outcome
Tumor Microenvironment
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Abstract Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have revealed that a remarkable level of genetic, epigenetic, and environmental heterogeneity exists within each individual glioma. Together, these interconnected layers of intratumoral heterogeneity result in extreme phenotypic heterogeneity at the cellular level, providing for multiple mechanisms of therapeutic resistance and forming a highly adaptable and resilient disease. In this review, we discuss how glioma intratumoral heterogeneity and malignant cellular state plasticity drive resistance to existing therapies and look to a future in which these challenges may be overcome. SIGNIFICANCE: Glioma intratumoral heterogeneity and malignant cell state plasticity represent formidable hurdles to the development of novel targeted therapies. However, the convergence of genotypically diverse glioma cells into a limited set of epigenetically encoded transcriptional cell states may present an opportunity for a novel therapeutic strategy we call "State Selective Lethality." In this approach, cellular states (as opposed to genetic perturbations/mutations) are the subject of therapeutic targeting, and plasticity-mediated resistance is minimized through the design of cell state "trapping agents."
AbstractList Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have revealed that a remarkable level of genetic, epigenetic, and environmental heterogeneity exists within each individual glioma. Together, these interconnected layers of intratumoral heterogeneity result in extreme phenotypic heterogeneity at the cellular level, providing for multiple mechanisms of therapeutic resistance and forming a highly adaptable and resilient disease. In this review, we discuss how glioma intratumoral heterogeneity and malignant cellular state plasticity drive resistance to existing therapies and look to a future in which these challenges may be overcome. SIGNIFICANCE: Glioma intratumoral heterogeneity and malignant cell state plasticity represent formidable hurdles to the development of novel targeted therapies. However, the convergence of genotypically diverse glioma cells into a limited set of epigenetically encoded transcriptional cell states may present an opportunity for a novel therapeutic strategy we call "State Selective Lethality." In this approach, cellular states (as opposed to genetic perturbations/mutations) are the subject of therapeutic targeting, and plasticity-mediated resistance is minimized through the design of cell state "trapping agents."
Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have revealed that a remarkable level of genetic, epigenetic, and environmental heterogeneity exists within each individual glioma. Together, these interconnected layers of intratumoral heterogeneity result in extreme phenotypic heterogeneity at the cellular level, providing for multiple mechanisms of therapeutic resistance and forming a highly adaptable and resilient disease. In this review, we discuss how glioma intratumoral heterogeneity and malignant cellular state plasticity drive resistance to existing therapies and look to a future in which these challenges may be overcome. SIGNIFICANCE: Glioma intratumoral heterogeneity and malignant cell state plasticity represent formidable hurdles to the development of novel targeted therapies. However, the convergence of genotypically diverse glioma cells into a limited set of epigenetically encoded transcriptional cell states may present an opportunity for a novel therapeutic strategy we call "State Selective Lethality." In this approach, cellular states (as opposed to genetic perturbations/mutations) are the subject of therapeutic targeting, and plasticity-mediated resistance is minimized through the design of cell state "trapping agents."Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have revealed that a remarkable level of genetic, epigenetic, and environmental heterogeneity exists within each individual glioma. Together, these interconnected layers of intratumoral heterogeneity result in extreme phenotypic heterogeneity at the cellular level, providing for multiple mechanisms of therapeutic resistance and forming a highly adaptable and resilient disease. In this review, we discuss how glioma intratumoral heterogeneity and malignant cellular state plasticity drive resistance to existing therapies and look to a future in which these challenges may be overcome. SIGNIFICANCE: Glioma intratumoral heterogeneity and malignant cell state plasticity represent formidable hurdles to the development of novel targeted therapies. However, the convergence of genotypically diverse glioma cells into a limited set of epigenetically encoded transcriptional cell states may present an opportunity for a novel therapeutic strategy we call "State Selective Lethality." In this approach, cellular states (as opposed to genetic perturbations/mutations) are the subject of therapeutic targeting, and plasticity-mediated resistance is minimized through the design of cell state "trapping agents."
Author Fine, Howard A.
Nicholson, James G.
Author_xml – sequence: 1
  givenname: James G.
  orcidid: 0000-0002-4585-6924
  surname: Nicholson
  fullname: Nicholson, James G.
– sequence: 2
  givenname: Howard A.
  surname: Fine
  fullname: Fine, Howard A.
BackLink https://www.ncbi.nlm.nih.gov/pubmed/33558264$$D View this record in MEDLINE/PubMed
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Snippet Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent...
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StartPage 575
SubjectTerms Animals
Biological Variation, Population
Biomarkers, Tumor
Clinical Decision-Making
Combined Modality Therapy
Disease Management
Disease Susceptibility
Drug Resistance, Neoplasm
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Glioma - diagnosis
Glioma - etiology
Glioma - therapy
Humans
Neoplasm Grading
Neoplasm Staging
Prognosis
Treatment Outcome
Tumor Microenvironment
Title Diffuse Glioma Heterogeneity and Its Therapeutic Implications
URI https://www.ncbi.nlm.nih.gov/pubmed/33558264
https://www.proquest.com/docview/2487746852
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