Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas.

Autor: von Knebel Doeberitz N; Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Paech D; Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Neuroradiology, Bonn University Hospital, Bonn, Germany., Sturm D; Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany.; Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany., Pusch S; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.; German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Turcan S; Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany., Saunthararajah Y; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2022 Nov 01; Vol. 151 (9), pp. 1431-1446. Date of Electronic Publication: 2022 Jun 16.
DOI: 10.1002/ijc.34131
Abstrakt: Glial-lineage malignancies (gliomas) recurrently mutate and/or delete the master regulators of apoptosis p53 and/or p16/CDKN2A, undermining apoptosis-intending (cytotoxic) treatments. By contrast to disrupted p53/p16, glioma cells are live-wired with the master transcription factor circuits that specify and drive glial lineage fates: these transcription factors activate early-glial and replication programs as expected, but fail in their other usual function of forcing onward glial lineage-maturation-late-glial genes have constitutively "closed" chromatin requiring chromatin-remodeling for activation-glioma-genesis disrupts several epigenetic components needed to perform this work, and simultaneously amplifies repressing epigenetic machinery instead. Pharmacologic inhibition of repressing epigenetic enzymes thus allows activation of late-glial genes and terminates glioma self-replication (self-replication = replication without lineage-maturation), independent of p53/p16/apoptosis. Lineage-specifying master transcription factors therefore contrast with p53/p16 in being enriched in self-replicating glioma cells, reveal a cause-effect relationship between aberrant epigenetic repression of late-lineage programs and malignant self-replication, and point to specific epigenetic targets for noncytotoxic glioma-therapy.
(© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Databáze: MEDLINE
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