Abstract A34: Development of a drug sensitivity testing pipeline towards the establishment of precision medicine for ovarian cancer
Authors: Hirasawa Akira , Murumägi Astrid , Yadav Bhagwan , Mpindi John Patrick , Mariliina Arjama , Aittokallio Tero , Wennerberg Krister , Aoki Daisuke , Kallioniemi Olli 
Published: August 2014

Ovarian cancer (OC) has the highest mortality rate among all malignant tumors of the female genital tract. There is a pressing need for targeted drugs with better anti-cancer selectivity, particularly in patients with platinum-refractory and recurrent OC. Less than 20% of such patients respond to conventional cytotoxic chemotherapy regimens.

Compared to other cancers, molecularly targeted drugs are seldom used for the treatment of any OC. Thus, there is an urgent need to develop better understanding of the drug sensitivity in OC, particularly in the clear cell and mucinous subtypes, which tend to be resistant to platinum-based regimens, in order to improve survival and to facilitate precision medicine approaches to therapy. Large-scale studies using cancer cell lines (Barretina J et al. Nature, 2012; Garnett MJ et al. Nature, 2012.) have been proposed to help in identifying links between genomic changes and drug sensitivity. While OC has been included in such studies, the number of OC cases is still small, and most samples come from the common serous subtype.

In order to discover previously unsuspected anti-cancer capabilities of approved or emerging drugs, we have established a Drug Sensitivity and Resistance Testing pipeline for 280 cancer drugs (Pemovska et al., manuscript, 2013). Here, the DSRT platform was applied to analyze 25 OC cell lines and 2 cell lines from ovarian surface epithelial cells. Cell lines were plated in 384-well plates where drugs had been pre-printed using acoustic nano-dispensing technology (Labcyte®) each in five doses over a concentration range spanning 5 logs. The panel covered drugs approved by the Food and Drug Administration, European Medicine Agency, or Pharmaceuticals and Medical Devices Agency as well as emerging, investigational, and pre-clinical oncology compounds such as kinase and non-kinase inhibitors. Cell viability was measured using Cell Titer Glow® luminescence assays at 3 days. Analysis of quantitative dose-response curves using Dotmatics® software was applied to measure 50% inhibitory concentrations (IC50) values. The area under the curve was estimated from the dose-response curve of each compound and was compared across all samples to obtain the drug sensitivity score (DSS) (Yadav et al., manuscript, 2013).

Bioinformatics processing of the data from OC cell lines resulted in several key observations. Importantly, we found many emerging, currently not-yet-approved drugs in several OC cell lines, including both kinase (e.g. phospho-receptor tyrosine kinases, checkpoint and mitotic kinases, Raf kinases, mitogen-activated protein kinase kinase, janus kinases, mammalian target of rapamycin, phosphoinositide 3-kinase) as well as non-kinase (e.g., histone deacetylase inhibitors, and poly (ADP-ribose) polymerase) drugs. The molecular predictors of efficacy of these drugs are being explored by correlating DSRT data with the genomics and transcriptomics data of the OC cell lines.

In summary, several emerging anti-cancer drugs show potential in subsets of OC cell lines, according to data from direct testing of drug efficacy. The DSRT pipeline could be a powerful novel strategy for assessing OC drug response in OC cell models. Correlations with genomic data could yield new translational and pharmacogenomic opportunities for OC.

Citation Format: Akira Hirasawa, Astrid Murumägi, Bhagwan Yadav, John Patrick Mpindi, Arjama Mariliina, Tero Aittokallio, Krister Wennerberg, Daisuke Aoki, Olli Kallioniemi. Development of a drug sensitivity testing pipeline towards the establishment of precision medicine for ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A34.