Key Concepts in Glioblastoma Therapy
Key Concepts in Glioblastoma Therapy
From a broader perspective, the status of the molecular machinery that detects, signals and repairs DNA damage, and overall orchestrates the multifaceted cellular response to genotoxic insults (here referred to as the DNA damage response: 'DDR') critically impacts tumour development and clinical outcome. While this is arguably relevant for any type of tumour to some extent, the DDR concept is particularly important for glioblastomas for the following reasons. First, the standard-of-care non-surgical modalities used to treat glioblastomas, namely ionising radiation and TMZ-based chemotherapy, operate through their genotoxic effects by causing mainly DNA double strand breaks (DSBs) and alkylated DNA lesions, respectively. Therefore, each individual patient's germ-line disposition of the DDR-related genes, along with any somatic alterations within the DDR machinery that have been selectively acquired by the tumour dictate (along with other factors such as the tumour microenvironment discussed above) their response to therapy. Second, among the hallmarks of glioblastomas is their resistance to radiotherapy and chemotherapy. These phenomena highlight the intimate involvement of the cellular DDR network, particularly DNA damage signalling, cell-cycle checkpoints and DNA repair pathways, in the pathobiology of glioblastomas. Third, the harmful side effects of the standard therapies, including brain damage and consequently cognitive changes, are also attributable to DNA damage and the cellular and tissue responses to such treatments. Fourth, genetic and/or epigenetic aberrations of a range of DDR factors, including the above mentioned p53 tumour suppressor or DNA repair genes such as MGMT, occur commonly during glioblastoma pathogenesis and/or upon treatment. This aspect of gliomagenesis has been suspected and partly known for years, however it has only been validated by the recent insights gained through comprehensive analyses by complete tumour genome sequencing within the framework of the TCGA initiative. Finally, the TICs (see concept 4), appear to be particularly resistant to DNA-damaging therapies. This resistance is, at least in part, due to enhanced DNA damage signalling and checkpoint machinery.
Conceptually very relevant for such DDR-related features of gliomas is the recently described strong, constitutive activation of the DDR signalling pathways, observed from the early stages (grade II gliomas) of gliomagenesis up to glioblastomas. This spontaneous DDR activation precedes any genotoxic treatment, and it appears to be even more pronounced in gliomagenesis than in early lesions of major epithelial tumour types, in which this phenomenon represents a candidate intrinsic barrier against activated oncogenes and tumour progression. A major source of such DDR activation in early lesions including low-grade gliomas appears to be oncogene-induced replication stress, while in later stages of tumour progression, particularly in glioblastomas, the constitutive DNA damage signalling is fuelled by continued replication stress and by enhanced oxidative stress. Biologically, such oncogene-evoked DDR activation often leads to cell death or permanent proliferation arrest known as cellular senescence. This activation eliminates nascent tumour cells from the proliferative pool, thereby delaying or preventing tumour progression. Those lesions that do progress in the face of such constitutively activated DDR often do so by selection of various defects along the DDR signalling or effector pathways, such as mutations in the ATM-Chk2-p53 DDR pathway. Importantly, while such selected DDR aberrations facilitate tumour progression by allowing escape from DDR-induced senescence or apoptosis, the very same defects may create tumour-specific vulnerabilities that can be exploited by therapeutic strategies based on the synthetic lethality principle (see concept 2 above).
In terms of exploiting the status of the DDR machinery for glioblastoma therapies, two major avenues are under intensive research and validation. First, there are promising attempts to sensitise glioblastoma cells (including the more resistant TICs) to conventional genotoxic therapy, such as ionising radiation, by concomitantly inhibiting the DNA damage signalling to downstream checkpoint and repair effectors. This strategy relies mainly on small molecule inhibitors of DDR kinases ATM, ATR, Chk1 and Chk2. This strategy appears particularly suitable for tumours with mutant p53. Such cancer cells lack the major p53-dependent G1/S checkpoint, and upon inhibition of the DDR kinases (whose activity underlies the still operational G2/M checkpoint) enter mitosis with an overload of unrepaired DNA damage, both endogenous and therapy induced, followed by cell death. An analogous strategy to overload glioblastoma cells with unrepaired DNA damage involves TMZ treatment with concurrent inhibition of MGMT in those cases where the MGMT gene promoter is not methylated.
An emerging alternative treatment strategy takes advantage of the synthetic lethality and the accumulated knowledge about the DDR mechanisms. This strategy exploits tumour-selective defects in certain DNA repair pathways, such as DSB repair, by homologous recombination (HR). HR is a mechanism to copy a DNA sequence from an intact DNA molecule (mainly from the newly synthesised sister chromatid) to bypass or repair replication-associated DNA lesions. This promising strategy exploits HR defects that are found in some tumours. These HR-deficient tumours are particularly dependent on other repair processes to avoid the generation of DSBs. These tumour cells are therefore particularly sensitive to inhibition of these other repair processes. Such a strategy has shown promise in preclinical studies in which breast tumour cells defective to HR appear hypersensitive to inhibition of base excision repair by small molecule inhibitors of poly(ADP-ribose) polymerase (PARP). Of note, PARP inhibition has shown promise in glioblastoma treatment in cell culture models. and several PARP inhibitors are under investigation in clinical glioblastoma trials.
Concept 7: DNA Damage Response
From a broader perspective, the status of the molecular machinery that detects, signals and repairs DNA damage, and overall orchestrates the multifaceted cellular response to genotoxic insults (here referred to as the DNA damage response: 'DDR') critically impacts tumour development and clinical outcome. While this is arguably relevant for any type of tumour to some extent, the DDR concept is particularly important for glioblastomas for the following reasons. First, the standard-of-care non-surgical modalities used to treat glioblastomas, namely ionising radiation and TMZ-based chemotherapy, operate through their genotoxic effects by causing mainly DNA double strand breaks (DSBs) and alkylated DNA lesions, respectively. Therefore, each individual patient's germ-line disposition of the DDR-related genes, along with any somatic alterations within the DDR machinery that have been selectively acquired by the tumour dictate (along with other factors such as the tumour microenvironment discussed above) their response to therapy. Second, among the hallmarks of glioblastomas is their resistance to radiotherapy and chemotherapy. These phenomena highlight the intimate involvement of the cellular DDR network, particularly DNA damage signalling, cell-cycle checkpoints and DNA repair pathways, in the pathobiology of glioblastomas. Third, the harmful side effects of the standard therapies, including brain damage and consequently cognitive changes, are also attributable to DNA damage and the cellular and tissue responses to such treatments. Fourth, genetic and/or epigenetic aberrations of a range of DDR factors, including the above mentioned p53 tumour suppressor or DNA repair genes such as MGMT, occur commonly during glioblastoma pathogenesis and/or upon treatment. This aspect of gliomagenesis has been suspected and partly known for years, however it has only been validated by the recent insights gained through comprehensive analyses by complete tumour genome sequencing within the framework of the TCGA initiative. Finally, the TICs (see concept 4), appear to be particularly resistant to DNA-damaging therapies. This resistance is, at least in part, due to enhanced DNA damage signalling and checkpoint machinery.
Conceptually very relevant for such DDR-related features of gliomas is the recently described strong, constitutive activation of the DDR signalling pathways, observed from the early stages (grade II gliomas) of gliomagenesis up to glioblastomas. This spontaneous DDR activation precedes any genotoxic treatment, and it appears to be even more pronounced in gliomagenesis than in early lesions of major epithelial tumour types, in which this phenomenon represents a candidate intrinsic barrier against activated oncogenes and tumour progression. A major source of such DDR activation in early lesions including low-grade gliomas appears to be oncogene-induced replication stress, while in later stages of tumour progression, particularly in glioblastomas, the constitutive DNA damage signalling is fuelled by continued replication stress and by enhanced oxidative stress. Biologically, such oncogene-evoked DDR activation often leads to cell death or permanent proliferation arrest known as cellular senescence. This activation eliminates nascent tumour cells from the proliferative pool, thereby delaying or preventing tumour progression. Those lesions that do progress in the face of such constitutively activated DDR often do so by selection of various defects along the DDR signalling or effector pathways, such as mutations in the ATM-Chk2-p53 DDR pathway. Importantly, while such selected DDR aberrations facilitate tumour progression by allowing escape from DDR-induced senescence or apoptosis, the very same defects may create tumour-specific vulnerabilities that can be exploited by therapeutic strategies based on the synthetic lethality principle (see concept 2 above).
In terms of exploiting the status of the DDR machinery for glioblastoma therapies, two major avenues are under intensive research and validation. First, there are promising attempts to sensitise glioblastoma cells (including the more resistant TICs) to conventional genotoxic therapy, such as ionising radiation, by concomitantly inhibiting the DNA damage signalling to downstream checkpoint and repair effectors. This strategy relies mainly on small molecule inhibitors of DDR kinases ATM, ATR, Chk1 and Chk2. This strategy appears particularly suitable for tumours with mutant p53. Such cancer cells lack the major p53-dependent G1/S checkpoint, and upon inhibition of the DDR kinases (whose activity underlies the still operational G2/M checkpoint) enter mitosis with an overload of unrepaired DNA damage, both endogenous and therapy induced, followed by cell death. An analogous strategy to overload glioblastoma cells with unrepaired DNA damage involves TMZ treatment with concurrent inhibition of MGMT in those cases where the MGMT gene promoter is not methylated.
An emerging alternative treatment strategy takes advantage of the synthetic lethality and the accumulated knowledge about the DDR mechanisms. This strategy exploits tumour-selective defects in certain DNA repair pathways, such as DSB repair, by homologous recombination (HR). HR is a mechanism to copy a DNA sequence from an intact DNA molecule (mainly from the newly synthesised sister chromatid) to bypass or repair replication-associated DNA lesions. This promising strategy exploits HR defects that are found in some tumours. These HR-deficient tumours are particularly dependent on other repair processes to avoid the generation of DSBs. These tumour cells are therefore particularly sensitive to inhibition of these other repair processes. Such a strategy has shown promise in preclinical studies in which breast tumour cells defective to HR appear hypersensitive to inhibition of base excision repair by small molecule inhibitors of poly(ADP-ribose) polymerase (PARP). Of note, PARP inhibition has shown promise in glioblastoma treatment in cell culture models. and several PARP inhibitors are under investigation in clinical glioblastoma trials.
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