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Eng et al. J Cancer Metastasis Treat 2019;5:69 I http://dx.doi.org/10.20517/2394-4722.2019.021 Page 9 of 13

cell lung cancer (SCLC), lymphoma, multiple myeloma, renal cell carcinoma and melanoma, also showed
[97]
promising anti-cancer results . Given that a subset of miRNAs mediate the crosstalk between autophagy
and metastatic states of cancer cells, we postulate that the miRNA-autophagy-metastasis axis of cancer
could be effectively targeted by the precise in vivo delivery of specific combinations of miRNA therapeutics
(involving miRNAs depicted in Figures 1 and 2), which could improve the clinical trajectory of late stage
cancers. Alternatively, blockade of the biogenesis of oncomiRs via small-molecule RNA ligands has also
[98]
been reported to be a feasible anti-cancer approach . These small molecules consist of high affinity RNA
binding motives, including the aminoglycoside neomycin and different natural and artificial nucleobases,
that target pri-miRNAs of oncogenic miR-372/miR-373 and inhibit Dicer-mediated maturation of these
miRNAs to elicit anti-proliferative effects on gastric cancer cells.

Apart from miRNA therapeutics, siRNA therapeutics that target a number of driver oncogenes like c-Myc,
PD-L1/2, mutant KRAS, PKN3, EphA2, LMP2/7, MECL1, APN401 and PLK1 have also been shown to
exhibit on-target anti-cancer effects and elicit little or no overt toxicities in humans in a number of Phase
I clinical trials (NCT00306904, NCT02314052, NCT02528682, NCT01676259, NCT01808638, NCT01591356,
NCT00672542, NCT02166255 and NCT01437007). We envisage that delivery of siRNAs targeting genes
that are important for autophagy and metastasis of cancer cells could also be a viable therapeutic route to
combat late stage cancers.

CONCLUSION
Alterations in key cellular processes, including cell adhesive properties and autophagy, promote tumor cell
dissemination and colonization at distant organs/tissues. These processes are mediated by a vast network of
miRNAs that has the propensity to crosstalk with each other. Striking this Achilles heel of cancer precisely
via specific combinations of miRNA therapeutics could dramatically improve the survival outcomes of
cancer patients. Future work should be focused on tissue-specific targeting delivery vehicles, which carry
miRNA therapeutics or other payloads, so as to avoid potential toxicities and off-target effects.

DECLARATIONS
Authors’ contributions
Manuscript writing: Eng GWL, Kok VJT, Cheong JK

Availability of data and materials
Not applicable.

Financial support and sponsorship
Eng GWL is supported by the Singapore Ministry of Education Postdoctoral Fellowship. Kok VJT
is supported by the Singapore Ministry of Education (MOE) Academic Research Fund (AcRF) Tier
2 grant (MOE2016-T2-2-052). Cheong JK is supported by the Singapore MOE AcRF Tier 2 grant
(MOE2016-T2-2-052) and a startup grant from the Medical Sciences Cluster of Yong Loo Lin School of
Medicine, National University of Singapore.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.