Introduction

Pancreatic cancer, one of the most lethal malignancies, currently has limited effective therapeutic options. This has resulted in a dismal five-year survival rate of approximately 10%. Traditional chemotherapeutic strategies often fail largely due to advanced stage at diagnosis and resistance to conventional treatment methods. Recognizing this critical need, our research focuses on the development of novel epigenetic therapies for pancreatic cancer. Pancreatic cancer management presents significant challenges due to late-stage diagnosis, aggressive tumor biology, and limited efficacy of existing treatment options. Our study explores a small molecule combination to induce epigenetic reprogramming as a potential therapeutic strategy. We demonstrate that treatment with a combination of romidepsin, a histone deacetylase (HDAC) inhibitor and des-methyl pateamine A (DMPatA), a protein synthesis inhibitor, initiates modulation of the histone code, with unexpected persistent H3K9 and H3K27 acetylation. It induces global transcription and causes DNA damage, which results in a synergistic anti-proliferative response in pancreatic cancer cells. 

Methods

Combining romidepsin with DMPatA is synergistic in inhibiting cell proliferation in PDAC cells. Excess over Bliss synergy analysis was used to test the anticancer effect of combining various concentrations of romidepsin with DMPatA at 2nM. Analysis confirmed increased synergy at lower concentrations. C. Cytotoxicity graphs showing the effect of romidepsin alone, DMPatA alone at 2nM, and combination of romidepsin with DMPatA at 2nM. Romidepsin treatment was only for 6- hours.

Combination of romidepsin and DMPatA exhibits antitumor effect in xenograft model of MiaPaCa-2. A. MiaPaCa-2 xenograft model with flank injections of the MiaPaCa-2 cell line were randomly divided into treatment with vehicle control, romidepsin, DMPatA, and combinations with two different doses of romidepsin. Tumor growth was significantly reduced in mice treated with the combination compared to vehicle control and the single agents. No significant changes were observed in the weight of mice treated with the combination and single agents indicating the safety of the tested doses in the animals.

Results

Treatment with the combination demonstrates efficacy in inhibiting tumor growth in a xenograft mouse model of pancreatic cancer. Our studies into the mechanism of this combination treatment show the increase in global transcription is associated with significant R-loop accumulation that may contribute to the observed DNA damage and genome instability. Further, the combination treatment causes a significant reduction in the cellular acetyl-CoA levels, as well as a decrease in levels of c-MYC protein and its targets, and impairment of both glycolysis and OXPHOS processes. Forced overexpression of MYC appears to increase the sensitivity of pancreatic cells to this treatment, potentially indicating a therapeutic advantage for MYC-overexpressing/MYC-addicted PDAC tumors. Overall, the enhanced toxicity in cancer cells post-treatment with the combination appears to be driven by a simultaneous increase in genomic instability and a decrease in ATP production. In this poster, we report the novel and scalable synthesis of DMPatA as well as new syntheses of key fragments C, D, F and G.

Conclusion

Our results suggest that combining the HDAC inhibitor, romidepsin, with the eIF4A inhibitor MZ735, may offer a promising strategy as a novel epigenetic therapy for pancreatic cancer. This combination shows significant antitumor activity in both in vitro and in vivo models of pancreatic cancer. Our study highlights the value of targeting epigenetic modifications in cancer therapy. Further studies are required to fully understand the mechanism of action and optimal doses to facilitate the translation of these findings into the clinic.