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alone by mAbs and enhanced the antitumor effect of techniques of executing RNAi: nuclear delivery of
[46]
doxorubicin in a colorectal cancer model. [47] gene expression constructs to express shRNA and
cytoplasmic delivery of siRNA. Silencing by synthetic
However, the development of resistance to TKIs makes siRNA, RNA oligonucleotides 21-23 nucleotides long,
their therapeutic use quite challenging. [48] Overexpression is more expedient than shRNA due to the diffi culty
of PDGFα in cells has been found to be responsible for [53]
acquiring resistance against BMS-754807. Different of constructing shRNA expression systems and the
[54]
mechanisms have been identifi ed which account for requirement for nuclear delivery. The potential gene
TKI resistance (both acquired and inherent) in cancer silencing ability of siRNAs in animal models has made
cells. These are: (1) somatic, genetic or epigenetic them promising investigational drug candidates and some
mutations within kinase domains; (2) overexpression and siRNAs are in clinical trials. However, no siRNA against
amplifi cation of GFRs genes to overrule the inhibitors’ GFRs have been approved yet for cancer treatment.
function; (3) modifi cations in signaling pathways to There are few siRNAs against GFRs, which have been
bypass the signal mediated by specifi c receptor; and used in cell culture and animal models [Table 5]. The
(4) overexpression of ATP-binding cassette transporters primary challenge to the clinical use of RNAi is the
proteins (ABC-transporters) which transport TKIs need to deliver a relatively small molecule in suffi cient
outside of cells, limiting achievable intracellular quantities to tumor cells after systemic administration.
concentrations. Nucleic acid therapeutics delivery is an area of very
active investigation.
TKIs with broad spectrum activity that inhibit a
number of GFRs are less specifi c but often more Concerns and Future Perspectives
effective compared to highly specifi c inhibitors. For The anionic nature of siRNA prevents it diffusion
example, a multi-targeted TKI against VEGFR, PDGFR through cellular membrane posing a diffi culty in
and FGFR (TKI258) is more potent in inhibiting delivering siRNA into cells. Moreover, systemically
angiogenesis in pancreatic cancer cells as the signals administered naked siRNA is subjected to degradation
mediated by these three receptors are crucial for the by endogenous nucleases, renal clearance, and non-
blood vessels formation. [49] This inhibitor is effi cacious specifi c bio-distribution. Accordingly, a smart carrier
in delaying cancer growth and inhibiting metastasis in is essential for functional delivery of siRNAs into
a pancreatic cancer model [49] and clinically used for the system. A wide number of genetically engineered
advanced renal cell carcinoma and breast cancer. [50,51] viral vectors or synthetic polymer/liposome-based
Broad spectrum TKIs would be less susceptible to nanovectors are in use to deliver siRNAs in different
acquired resistance. cells and animal models. However, there remain
Nucleic acid-based therapeutics to block GFR concerns surrounding the safety and effi cacy of these
expression nanovectors. The successful clinical application of
siRNAs will require nanosized cargos with higher
The clinical applications of current chemotherapeutic binding affi nity for siRNAs and possibly other
drugs are often limited by their toxic effects on healthy drugs, fast release of bound siRNA in the cytoplasm,
dividing cells. Dose reductions due to toxicity can limit versatility to be engineered for targeting tumors, in vivo
effi cacy and select drug-resistant cancer cell clones. stability, lack of immunogenicity and minimal toxicity.
Advances in cancer molecular and cell biology have led A pH-sensitive inorganic carbonate apatite nanocarrier
to the identifi cation of numerous potentially actionable system has recently been developed that could provide
genes, not all of which encode druggable targets. an attractive solution to the challenges presented by
These genes and their transcripts are potential targets other carriers. This carrier has been used to transport
for nucleic acid therapeutics. Gene silencing both at siRNAs against ErbB2, IGF1R, and Bcl-2 genes as
transcriptional and translational levels is a promising well as wild-type p53 gene that inhibited the growth
tool to treat cancer more effectively. [52] Among available of established tumors in syngeneic mouse models. [56,58]
technologies, RNA interference (RNAi) using double This platform could be used to target one or more GFRs
stranded siRNA or short hairpin RNA (shRNA) is in tumors.
a promising candidate technology, provided that
pharmacokinetic obstacles to quantitative delivery are Conclusion
overcome.
Targeting multiple GFRs offers signifi cant therapeutic
RNAi is a biological posttranscriptional regulatory promise in cancer therapy. As overexpression of
process in which small endogenous RNA (microRNA) GFRs is also responsible for resistance to different
inhibit gene expression by hybridizing with mRNAs drugs, combination regimens may prevent or alleviate
and either causing their degradation or preventing resistance. Nanoparticles-mediated siRNA delivery
translation. Mimicking physiological RNAi, siRNAs may have signifi cant clinical applications once
are designed exogenously to deliver to cancer cells for clinically suitable delivery platforms are identifi ed and
selective mRNA targeting. There are two fundamental validated.

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 197