Abstract
Background: Melanoma is one of the most frequent causes of cancer death and despite significant treatment improvements, non-responder patients and those who develop resistance constitute a significant proportion of patients still in dire need of alternative and improved therapeutic options. Omomyc is a MYC inhibitor designed by Dr. Soucek that is extensively preclinically validated and currently being tested in a Phase I/IIa Clinical Trial. We have seen potent antitumour and antimetastatic effects when Omomyc is transgenically expressed in melanoma cells. Material and methods: We performed microarray analysis on BRAF-mutated A375 and BRAF wild-type SkMel147 human melanoma cells in vivo after one week of Omomyc expression and analysed them in R with Bioconductor. We assessed the overlap on transcriptional reprogramming exerted by Omomyc and investigated how these genes are associated with patient prognosis, by retrieving clinical and transcriptional data from the Skin Cutaneous Melanoma TCGA, PanCancer Atlas study in cBioPortal. Results: We found 620 differentially expressed genes in common, 436 downregulated by Omomyc (DN) and 184 upregulated (UP). DN genes cluster into Cell Cycle, RNA processing, Metabolism and Chromatin modification, organisation, and remodelling, while UP genes are related to Immune Response and several subcellular processes. Expression lower than the median of 45% of the DN genes or higher than the median of 54% of the UP genes are associated with significantly increased survival. We then generated a 6-gene signature combining DN and UP genes, that clearly separates patients in good and bad prognosis cohorts. Those with simultaneous low expression of these DN genes and high expression of these UP genes have significantly increased OS (205 (162-NA) vs. 42 (28– 63) months, p = 7 × 10−7) Additionally, 63% of UP genes are enriched in patients with Good Prognosis whereas 56% of DN genes are enriched in Poor Prognosis patients. Thus, Omomyc in vivo-regulated genes overlap considerably with those genes enriched in patients pointing to a reasonable similarity among in vivo results with Omomyc and clinical and transcriptional data from patients. Finally, pre-ranked GSEA in these patients showed that those with Good Prognosis have lower expression of MYC target genes and genes involved in melanoma relapse and metastases, and increased expression of Adaptive Immune Response. Conclusion: We show that specific gene sets reflecting decreased MYC transcriptional activity, restricted metastatic capacity and increased immune response are identified in Omomyc-expressing melanoma xenografts and indicate patients with Good Prognosis. We can therefore define an Omomyc-derived gene signature that clearly discriminates patients with different prognoses, whose transcriptional signatures resemble those of vehicle or Omomyc-expressing tumours in vivo. Conflict of interest: Ownership: L. Soucek and M. Beaulieu are cofounders and shareholders of Peptomyc, a company focused on developing Myc inhibitors for cancer treatment. M.F. Zacarias Fluck, S. Casacuberta-Serra, and J.R. Whitfield are shareholders of Peptomyc S.L.
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