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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 293

that FUS is down-regulated in prostate cancer, reducing the levels of an androgen receptor repressor. In
contrast, FUS levels are increased in advanced therapy resistant prostate cancer, suggesting that it may play
a different role in this late stage of the disease.

49. Targeting phospholipase C as a novel therapeutic option for the treatment of prostate cancer

1
1
1
Mohammad Alkheilewi , Andrea Mohr , Ralf Zwacka , Metodi Metodiev , Euphemia Leung ,
1
2
2
Michelle Van Rensburg , David Barker , Johannes Reynisson , Greg Brooke 1
2
2
1 Univeristy of Essex, Colchester, UK
2 University of Auckland, New Zealand
Prostate cancer (PCa) growth is driven by the androgen receptor and hence therapies often target this sig-
nalling axis. Although successful initially, the treatments invariably fail and the tumours progress to the
aggressive castrate resistant stage of the disease. There is therefore a great need for novel therapeutics for
castrate resistant disease. Thieno[2,3-b] pyridines anticancer compounds were discovered by virtual high
throughput screening as potential inhibitors of phospholipase C, which has been shown to promote tu-
mour growth and metastasis. These compounds have been previously demonstrated to be effective inhibi-
tors of breast cancer. Here we expanded the research by investigating the efficacy of these compounds on
PCa cell lines. Using growth assays, flow-cytometry analysis, florescent imaging and cell tracking assays
I have demonstrated that the compounds are potent inhibitors of PCa proliferation and motility. Impor-
tantly, some of the compounds show less activity in the non-tumorigenic control BPH1, suggesting that
these drugs are more specific for cancer cells. Interestingly, the drugs were also found to induce multi-nu-
cleation, G /M arrest and promote apoptosis. In conclusion, these compounds represent a novel therapeutic
2
approach for PCa and further work to assess their efficacy is warranted.

50. Nanodelivery of CYP26 inhibitors enhances the actions of retinoic acid in

neuroblastoma-derived tumour cells

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1
1
1
Shreya Shah , Maja Bilip , Mayuran Mathiyalakan , Aris Tagalakis , Stephen Hart ,
1
2
Claire Simons , Andrew W. Stoker 1
1 UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
2 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK
Neuroblastoma is a paediatric, sympathetic nervous system cancer in which the five-year survival of
high grade tumour patients remains poor. After multimodal treatments, patients receive residual disease
therapy with retinoic acid (RA), a natural, vitamin A-derived neural differentiation agent. While RA can
modestly improve survival, it is beset with challenges of effective dosing, toxicity and evolved resistance.
RA in particular suffers poor pharmacokinetics due to its rapid metabolism by CYP26 enzymes and these
enzymes are also thought to be responsible for some forms of RA resistance. RA efficacy might thus be
improved through CYP26 inhibition in tumour cells. Given the highly hydrophobic nature of many CYP26
inhibitors, we also hypothesized that inhibitor bioavailability may be further improved through liposomal
nanodelivery. Several RA metabolism-blocking agents (RAMBAs) exist as inhibitors of CYP26 enzymes,
but these have not so far been tested for their abilities to either increase neuroblastoma cell differentiation,
or enhance the suppression of cell growth in response to RA. Here we demonstrate that the bioavailability
of these hydrophobic RAMBAs can be facilitated using liposomal nanoparticles. In RA-treated neuroblas-
toma cell lines, we show that both ethanol-solubilized and liposome-loaded RAMBAs can successfully