Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma |
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| Institution: | 1. Stem Cell and Cancer Research Institute;;2. Department of Biochemistry and Biomedical Sciences;;3. Department of Surgery, McMaster University, Hamilton;;4. Donnelly Centre and Department of Molecular Genetics, University of Toronto, Toronto, Canada;;5. The Francis Crick Institute, University College London Institute, London, UK |
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| Abstract: | Intratumoral heterogeneity (ITH) has increasingly being described for multiple cancers as the root cause of therapy resistance. Recent studies have started to explore the scope of ITH in glioblastoma (GBM), a highly aggressive and fatal form of brain tumor, to explain its inevitable therapy resistance and disease relapse. In this review, we detail the emerging data that explores the extensive genetic, cellular and functional ITH present in GBM. We discuss current experimental models of human GBM recurrence and suggest harnessing new technologies (CRISPR-Cas9 screening, CyTOF, cellular barcoding, single cell analysis) to delineate GBM ITH and identify treatment-refractory cell populations, thus opening new therapeutic windows. We will also explore why current therapeutics have failed in clinical trials and how ITH can inform us on developing empiric therapies for the treatment of recurrent GBM. |
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