Abstract 2618: Gemcitabine based peptide conjugates: Overcoming the pitfalls of conventional therapies by targeted approaches

Abstract

Abstract Although gemcitabine has been proved to be a valuable ally against several types of cancer, it is characterized by some weaknesses that limit its anticancer potential. These limitations are mainly associated with gemcitabine rapid inactivation as well as the different types of resistance that are related with its use. We have previously shown that conjugation of gemcitabine to a ligand peptide (molecule GSG) enhanced its metabolic stability systemically and locally (within the cancer cell), and lead to improved efficacy in a castration resistant prostate cancer (CRPC) animal model. In order to refine our previous findings, a bioanalytical methodology based on mass spectrometry that allows the simultaneous monitoring of gemcitabine as well as its active (dFdCDP, dFdCTP) and inactive (dFdU) metabolites was developed in the context of this study. The balance of gemcitabine and its active/inactive metabolites was evaluated in in vitro and in vivo systems after treatment with gemcitabine or selected gemcitabine based peptide conjugates (GSG). Furthermore, since GSG's structure contains a potent agonist peptide of the GnRH-R we investigated whether it could have a central effect through the pituitary by performing testosterone measurements in animals dosed with GSG. Interestingly, GSG appears to offer metabolic advantages in comparison to gemcitabine, an important attribute if we had to overcome gemcitabine acquired resistance. In addition, GSG is a potent GnRH-R agonist based on our in vivo biomarker model, suggesting that testosterone ablation might also represent a key attribute of the mechanism of action for our conjugate of interest. These findings along with the targeted delivery nature of this approach could ameliorate the therapeutic status of gemcitabine and expand the use of gemcitabine based conjugates in other types of cancers. Citation Format: Constantin Tamvakopoulos, Theodoros Karampelas, Orestis Argyros. Gemcitabine based peptide conjugates: Overcoming the pitfalls of conventional therapies by targeted approaches. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2618. doi:10.1158/1538-7445.AM2015-2618