Abstract 266: The G-quadruplex ligand EMICORON potentiates the antitumor efficacy of chemotherapy on colon cancer experimental models
Authors: Porru Manuela , Artuso Simona , Pompili Luca , Caruso Carla , Bianco Armandodoriano , Mottolese Marcella , Amoreo Carla A. , Biroccio Annamaria , Leonetti Carlo 
Published: July 2016

Background. G-quadruplex (G4) structures, present at the telomeric ends of chromosomes and in the promoters of a wide range of genes important in cell signaling, gained interest as therapeutic targets and several small molecules able to bind and stabilize G4 structures have been developed. However, due to the poor drug-like properties and/or selectivity profile none of the G4 ligands has progressed through the drug discovery pipeline. Our group recently showed that the novel G4 ligand EMICORON exhibited a favourable pharmacological profile, was well tolerated in mice and elicited antitumor efficacy against advanced experimental models of colon cancer. Based on these results, our aim was to study the ability of EMICORON to increase the efficacy of the standard chemotherapy for human colon cancer.

Matherials and Methods. We assessed the in vitro cytotoxic activity of EMICORON in combination with SN-38, 5-Fluorouracil and Oxaliplatin by clonogenic and 3D tumor-spheroid formation assay on HT29 colon cancer cells. The combination index (CI) values indicating synergism (CI 0.9 1.2) was evaluated. In vivo experiments were performed in mice bearing HT29 tumors treated with Irinotecan followed by EMICORON in one or two cycles of administration. Moreover, efficacy of the standard FOLFIRI (5-Fluorouracil, Leucovorin and Irinotecan) or FOLFOX (5-Fluorouracil, Leucovorin and Oxaliplatin) was evaluated in two different colon cancer patient-derived xenografts (PDXs).

Results and conclusions. The exposure of HT29 cells to the combination of EMICORON with chemotherapeutics resulted strongly synergistic when the drugs were administered following the sequence SN-38→EMICORON, EMICORON→5-Fluoruracil or EMICORON→Oxaliplatin, while the opposite sequences were additive or slightly antagonistic. The high activity of SN-38 followed by EMICORON was confirmed in the HT29-formed spheroids. When mice bearing HT29 xenografts were treated with EMICORON or Irinotecan, a tumor weight inhibition (TWI) of 35 or 65% was observed respectively, while the treatment with Irinotecan followed by EMICORON resulted more effective with a TWI of 80%. This marked antitumor effect of the combination produced an increase in overall survival of mice of 85%. Interestingly, the administration of a second cycle of treatment produced an impressive increase of survival of mice to 114%. Then, we tested the efficacy of FOLFOX or FOLFIRI therapeutic regimens on two colon cancer PDXs and as expected these treatments were very effective in reducing the tumor mass and delaying the tumor regrowth, but the relapse of the disease was observed in all the mice. In conclusion, our results demonstrating that EMICORON is able to increase the potency of any single drug, provide a compelling argument to suggest that the integration of EMICORON in standard chemotherapeutic regimens could be a highly valuable strategy.

Citation Format: Manuela Porru, Simona Artuso, Luca Pompili, Carla Caruso, Armandodoriano Bianco, Marcella Mottolese, Carla A. Amoreo, Annamaria Biroccio, Carlo Leonetti. The G-quadruplex ligand EMICORON potentiates the antitumor efficacy of chemotherapy on colon cancer experimental models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 266.