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Page 294 Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18

enhance the actions of RA, generating increased cell differentiation, suppression of cell proliferation and
suppression of the neuroblastoma driver protein N-Myc. We propose that the nanodelivery of RAMBAs
may provide a new approach for effective enhancement of RA action in neuroblastoma, potentially revers-
ing some forms of CYP26-based RA resistance, and facilitating more selective tumour targeting of these
agents.

51. Acquisition of a mesenchymal phenotype in endometrial cancer through epigenetic
manipulation may contribute to therapeutic resistance

2
1
1
1
L. D. Ordonez , L. Blake , L. Margarit , D. Gonzalez , P. Rees , L. Francis , R. S. Conlan 1
1
3
1 Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School
2 Abertawe Bro Morgannwg University Health Board
3 College of Engineering, Swansea University
Endometrial cancer (EC) is the most common gynecological cancer and the fourth most common cancer
in females in the UK. Classified into two histotypes, Type I correlates with estrogen receptor-positivity (ER)
and good prognosis while Type II, presents as ER-negative, high-grade disease with poor prognosis. Despite
advances in treatment, intrinsic and acquired resistance is a major problem, hindering the effectiveness
of drugs in the clinic. A better understanding of the mechanisms that determines resistance could make
a significant impact. To investigate the role of epigenetic instability in driving cellular changes in EC we
utilized cell lines to model Type I (Ishikawa) and Type II (Hec50) treated in vitro with the de-methylation
drug 5-Aza-Cdr. Ishikawa were more sensitive to treatment than Hec50. Hec50 cells showed a higher pro-
portion of cells with mesenchymal morphology and sublethal doses of 5-Aza-Cdr for 96 hours resulted in
an increase in mesenchymal cells in both cell lines. These changes correlated with a decrease in E-cadherin
in Ishikawa and increase in N-cadherin in Hec50, suggesting partial epithelial-to-mesenchymal transition
(EMT). EMT has previously been shown to correlate with invasion and treated cells showed promoter de-
methylation of genes that contribute to invasion (MMP9, MMP12, CXCL12) in both cell lines, correlating
with biophysical alterations suggestive of increased cellular motility. Treated Hec50 were cultured for a fur-
ther four weeks and showed the mesenchymal population was the most prominent to remain, suggesting
that this population could contribute to resistance. In conclusion our work suggests that a mesenchymal
phenotype may be involved in intrinsic and acquired resistance to therapy in EC, with a subpopulation of
cells acquiring a partial transition, as a result of epigenetic manipulation, during early stages of treatment.
Such mechanisms, well documented in breast cancer, are targets for next generation drugs, which may
present advantageous therapeutic strategies in the uterus.

52. By-pass of irinotecan resistance by the potent topoisomerase I inhibitor LMP400

2
4
3
1
Jan Stenvang , Yves Pommier , Niels Frank Jensen , Mark Cushman , Mark Roger ,
1
Nils Brünner 1
1 University of Copenhagen, Institute of Drug Design and Pharmacology & Scandion Oncology, Copenhagen,
Denmark
2 Development Therapeutics Branch and laboratory for Molecular Pharmacology, Center for Cancer Research,
National Cancer Institute, NIH, Bethesda, MD, USA
3 Department of Medicinal Chemistry and Molecular Pharmacology, and The Purdue Center for Cancer Re-
search, Purdue University, West Lafayette, Indiana 47907, USA
4 Gibson Oncology, Miami, FL 33109, USA