Abstract 2604: Characterization of the activity and the mechanism of action of the new retinoid derivative ST5589 in pre-clinical models of lymphomas: involvement of MYC and cell cycle genes
Authors: Bernasconi Elena , Kwee Ivo , Rinaldi Andrea , Cascione Luciano , Ponzoni Maurilio , Vesci Loredana , Giannini Giuseppe , Stathis Anastasios , Zucca Emanuele , Gaudio Eugenio , Bertoni Francesco 
Published: May 2015

Innovative and effective treatments are necessary for lymphomas that are common and still deadly cancers for many patients. Atypical retinoids show cytotoxic activity in different pre-clinical tumor models even though their mechanism of action is still largely unclear. Here, we report activity and mechanistic data with ST5589 (adarotene derivative), an active representative of this new class of agents (1), in pre-clinical lymphoma models.

Methods. Cell lines from diffuse large B-cell lymphoma (DLBCL, n=17), mantle cell lymphoma (MCL, n=4), splenic marginal zone lymphoma (SMZL, n=3) underwent 72 hr exposure to increasing doses of ST5589 (Sigma Tau, Pomezia, IT) to assess anti-proliferative activity by MTT assay. Apoptosis was assessed by Annexin-V/7-AAD staining. Gene expression profiling (GEP) was done with Illumina HumanHT-12 Expression BeadChips at baseline on all cell lines and, in triplicate, on 1 ABC- (TMD8) and 1 GCB-DLBCL (DOHH2) cell line treated with 300 nM ST5589 or DMSO for 8 hrs. Cell lines with IC50 &lt; than the median were defined as sensitive. GEP/IC50 correlation was assessed by Pearson correlation. Differential expression analysis was performed with LIMMA, GSEA, Metacore.

Results. Median IC50 was 235 nM (91-2652) for all the cell lines without significant differences among histological subtypes or between GCB- and ABC-DLBCL: DLBCL, 269 (97-2652); GCB-DLBCL 250, (97-1684); ABC-DLBCL, 531 (181-2625); MCL, 237 (91-401); SMZL, 144 (135-203). ST5589 induced apoptosis in 4/5 DLBCL cell lines (DOHH2, TMD8, SU-DHL-2, VAL). GEP in two DLBCL treated with ST5589 or DMSO was performed, and ST5589 significantly affected transcripts involved in multiple cell cycle-related gene-sets. Aurora kinase A coding gene was one of the most down-regulated.

MYC translocation was associated with lower IC50 (P 0.045) and higher number of responders (P 0.021). Transcripts associated with resistance to ST5589 were significantly enriched of genes involved in MYD88/TLR/STAT3 signaling and MAPK pathway, while transcripts associated with sensitivity were enriched of MYC target genes, genes high in Burkitt lymphoma, and involved in cellular respiration, and proteoglycan biosynthesis.

Conclusions. ST5589 showed anti-proliferative and cytotoxic preclinical activity in lymphoma, affecting cell-cycle regulation. While MYD88, TLR, STAT3 and MAPK pathways activation correlated with reduced drug activity, MYC deregulation was associated with sensitivity to ST5589. Our data, together with direct cytotoxicity and immune-system mediated activity reported for the parent compound adarotene ST1926 (2), make ST5589 worth of further studies in MYC-driven lymphomas as a representative of the innovative therapeutic class of atypical retinoids.

References

1 Giannini et al. Bioorganic and Med Chemistry 2012, 20: 2405-15

2 Pisano et al. Proceedings AACR 2004 Abstract #2075

Citation Format: Elena Bernasconi, Ivo Kwee, Andrea Rinaldi, Luciano Cascione, Maurilio Ponzoni, Loredana Vesci, Giuseppe Giannini, Anastasios Stathis, Emanuele Zucca, Eugenio Gaudio, Francesco Bertoni. Characterization of the activity and the mechanism of action of the new retinoid derivative ST5589 in pre-clinical models of lymphomas: involvement of MYC and cell cycle genes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2604. doi:10.1158/1538-7445.AM2014-2604