targeting tumour-associated neovascular endothelial cells that overexpress α ν β 3 /α ν β 5
integrins, for which the Arg-Gly-Asp peptides used are ligands [73]. TUG1-DDS
treatment effectively repressed TUG1 and achieved more marked tumour weight
reduction than γ-secretase inhibitor treatment, the current lead strategy for therapeutically targeting Notch signalling in GBM [74, 75]. No TUG1- nor Notch1-positive
tumours remained following TUG1-DDS treatment, and the GSC populations of
the tumours were almost fully eliminated [68] (Fig. 2b).
Given that inhibition of Notch cleavage by γ-secretase is the current focus of
GBM-targeted therapy development, these findings imply that targeting TUG1 with
anti-TUG1 ASOs specifically delivered to the GSC niche might be a safer, more
potent and more specific treatment strategy to target the same signalling pathway.
Therefore, taken together, not only do the findings of this study represent a major
advance towards the future development of implementable lncRNA-targeting
therapeutic agents per se but also make an unprecedentedly strong case for
prioritising the development of a lncRNA inhibition approach to signalling pathway
shutdown over developing a conventional small molecule approach to inhibit a
protein component of the same cancer-driving pathway.
5 Conclusion and Future Perspectives
The realisation that epigenetic traits are reversible and dynamically regulated was
swiftly followed by the development of small molecule inhibitors of “epi-enzymes”,
the first generation of “epidrugs” developed to correct epigenetic deregulation in
human disease [76]. Many have been developed into mainstream therapeutic agents,
including bromodomain inhibitors against epigenetic readers [77]; inhibitors against
the erasers of acetyl marks, HDACs [78]; and inhibitors of the catalytic components
of histone writer complexes such as EZH2 in PRC2 [79]. While moderately effective
in some cases, epi-enzyme inhibitors are generally limited in their use. This is
because they inhibit components of the epigenetic machinery that act globally, so
the blockade of their activity affects the distribution of the marks written, erased or
acted upon across the whole genome, not only at the specific genomic sites that
undergo disease-provoking epigenetic deregulation. Also, because many epigenetic
proteins act in complexes, inhibition of one component can have secondary effects
on other epigenetic proteins that are not direct targets for inhibition [76]. Moreover,
widespread transcriptomic changes corresponding with the sweeping global
epigenetic alterations brought about by epi-enzyme inhibitors would not only affect
protein-coding genomic loci but would also occur in the non-coding genome. Such
transcriptional perturbations may in turn affect the expression levels of lncRNAs that
are themselves involved in epigenetic regulation, further convoluting the indirect
epigenetic consequences of epi-enzyme inhibition. Therefore, the first generation
of epigenetic therapy agents are blunt tools for correcting epigenetic defects, and
their effectiveness in treating any given disease inevitably depends on the extent
to which the global epigenetic changes they induce preferentially lead to diseaseameliorative changes in the epigenetic landscape over disease-worsening ones.
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
417
integrins, for which the Arg-Gly-Asp peptides used are ligands [73]. TUG1-DDS
treatment effectively repressed TUG1 and achieved more marked tumour weight
reduction than γ-secretase inhibitor treatment, the current lead strategy for therapeutically targeting Notch signalling in GBM [74, 75]. No TUG1- nor Notch1-positive
tumours remained following TUG1-DDS treatment, and the GSC populations of
the tumours were almost fully eliminated [68] (Fig. 2b).
Given that inhibition of Notch cleavage by γ-secretase is the current focus of
GBM-targeted therapy development, these findings imply that targeting TUG1 with
anti-TUG1 ASOs specifically delivered to the GSC niche might be a safer, more
potent and more specific treatment strategy to target the same signalling pathway.
Therefore, taken together, not only do the findings of this study represent a major
advance towards the future development of implementable lncRNA-targeting
therapeutic agents per se but also make an unprecedentedly strong case for
prioritising the development of a lncRNA inhibition approach to signalling pathway
shutdown over developing a conventional small molecule approach to inhibit a
protein component of the same cancer-driving pathway.
5 Conclusion and Future Perspectives
The realisation that epigenetic traits are reversible and dynamically regulated was
swiftly followed by the development of small molecule inhibitors of “epi-enzymes”,
the first generation of “epidrugs” developed to correct epigenetic deregulation in
human disease [76]. Many have been developed into mainstream therapeutic agents,
including bromodomain inhibitors against epigenetic readers [77]; inhibitors against
the erasers of acetyl marks, HDACs [78]; and inhibitors of the catalytic components
of histone writer complexes such as EZH2 in PRC2 [79]. While moderately effective
in some cases, epi-enzyme inhibitors are generally limited in their use. This is
because they inhibit components of the epigenetic machinery that act globally, so
the blockade of their activity affects the distribution of the marks written, erased or
acted upon across the whole genome, not only at the specific genomic sites that
undergo disease-provoking epigenetic deregulation. Also, because many epigenetic
proteins act in complexes, inhibition of one component can have secondary effects
on other epigenetic proteins that are not direct targets for inhibition [76]. Moreover,
widespread transcriptomic changes corresponding with the sweeping global
epigenetic alterations brought about by epi-enzyme inhibitors would not only affect
protein-coding genomic loci but would also occur in the non-coding genome. Such
transcriptional perturbations may in turn affect the expression levels of lncRNAs that
are themselves involved in epigenetic regulation, further convoluting the indirect
epigenetic consequences of epi-enzyme inhibition. Therefore, the first generation
of epigenetic therapy agents are blunt tools for correcting epigenetic defects, and
their effectiveness in treating any given disease inevitably depends on the extent
to which the global epigenetic changes they induce preferentially lead to diseaseameliorative changes in the epigenetic landscape over disease-worsening ones.
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
417