Exploration of the pharmacodynamic profile of Acelarin, a novel ProTide drug, in an in vitro model of ovarian cancer

Abstract

Although most women with ovarian cancer initially respond to platinum-based therapy, overall survival is poor with only 45% of women alive 5 years after diagnosis. Gemcitabine, a fluoropyrimidine analogue often used when relapse occurs, shows limited additional survival benefit due to intrinsic and acquired resistance. Therefore, chemoresistance remains a burden for the treatment of these patients. Acelarin, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is currently in a Phase II trial for ovarian cancer. To date, it is showing clinically significant anti-tumour activity, even in patients who were not responsive to gemcitabine or relapsed. Understanding its mode of action may help to improve its efficacy and determine a biomarker for clinical response. A panel of ovarian cancer cell lines was used to compare the mode of action of Acelarin and gemcitabine. Combination of cisplatin and Acelarin was investigated in PE01 and PE04 cells, sensitive and resistant cell lines derived from a single patient who developed cisplatin resistance. DCK and DCTPP1 were previously identified as potential modulators of cancer cell sensitivity to Acelarin and could be used as predictive biomarkers.

Acelarin and gemcitabine displayed differences in cytotoxicity, delays in cell cycles and DNA damage. PE01 and PE04 cells responded differently to combination, depending on the order of the sequence. The pyrimidine metabolism pathway, through the regulation of nucleotide pools, modulated sensitivity to Acelarin. However, there was no correlation between DCK and DCTPP1 and patients’ response from a Phase I cohort treated with Acelarin.

Although similar in structure, Acelarin has a more targeted mechanism of action to induce cell death than gemcitabine. Repair mechanisms associated with platinumbased therapies resistance might potentiate Acelarin cytotoxicity. DCK and DCTPP1 are unlikely to either be of use as predictive biomarkers of clinical response to Acelarin.