Abstract B71: DEN-50R - establishment of a novel and unique cell line based drug screening platform for cancer treatment

Abstract

Today, chemotherapy and molecularly targeted therapies are the main therapeutic options in cancer treatment, but their effectiveness is limited by drug resistance, a major problem facing current cancer research. Since its establishment in the late 1980s, the NCI60 cell line panel has generated tremendous value, economic as well as societal, by contributing to the identification of mechanisms of drug action. This information, in turn, has been used to create new anti-cancer drugs for the benefit of patients. However, the cell lines comprised in the NCI60 panel are mostly derived from treatment of chemo-naïve patients (no medical treatment). Since early clinical trials of anti-cancer drugs most often recruit patients who have failed several different prior treatments, there is a need to develop a platform that builds on the concept underlying the NCI60 cell line panel and extend it to allow testing of potential new drugs in the setting of drug resistance. Moreover, it is also well-known that molecular drug resistance mechanisms might first appear following drug exposure and access to panels of matched drug-sensitive and drug-resistant isogenic cell lines, is thus mandatory for studying the underlying mechanisms of acquired drug resistance. We have initiated the establishment of DEN-50R, a novel and unique cell line-based drug screening platform within cancer treatment. The platform will, when fully developed, consist of human cancer cell lines representing the five most common cancer forms (colorectal, prostate, lung, breast cancer and malignant melanoma) and matched drug-resistant sublines for each of the five cancer forms. In a second phase additional cancer forms will be included. Resistance is developed against drugs and drug combinations currently used in the clinic, and with the introduction of novel drugs and regimens, new corresponding resistant sublines will be generated. All pairs of sensitive and resistant cell lines are thoroughly characterized with regard to cross-resistance to other drugs as well as to genomics, epigenomics, transcriptomics, and proteomics profiling. All data generated with the DEN-50R platform will be placed in the new National Danish Life Science Supercomputer with secure, regulated access providing a unique and innovative integrative analysis resource for academic, clinical and industrial researchers involved in anti-cancer drug development and cancer diagnostics at both pre-clinical and clinical levels. We envision that the DEN-50R be used to: • Test novel chemical entities for anti-cancer effects, including potential lack of cross-resistance thereby facilitating selection of analogs for further preclinical and clinical testing. • Test already known drugs for potential effects in drug resistant cell lines facilitating “repurposing” of drugs. • Reveal novel molecular drug resistant mechanisms allowing for targeted development of new drug entities that can circumvent drug resistance • identify novel predictive biomarkers for the most common drug entities further facilitating a personalized treatment approach. Citation Format: Jan Stenvang, Jose Moreira, Niels Frank Jensen, Signe Lykke Nielsen, Torben Orntoft, Ulrik Lassen, Cathrine Nordgaard, Stine Ninel Hansen, Haatisha Jandu, Anna Vind, Maria Andreasen, Camilla Cederbye, Julie Noer, Thiago Lima, Birgitte Martine Viuff, Soeren Brunak, Thomas Skoet Jensen, Peter Buhl Jensen, Joergen Drejer, Henrik Ditzel, Nils Brünner. DEN-50R - establishment of a novel and unique cell line based drug screening platform for cancer treatment. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B71.

The Pyrazolo[3,4-d]pyrimidine Derivative, SCO-201, Reverses Multidrug Resistance Mediated by ABCG2/BCRP

“…To identify potential new compounds that interfere with common drug resistance mechanisms, such as the overexpression of BCRP, we previously established the DEN-50R screening platform. This platform consists of isogenic pairs of drug-sensitive and drug-resistant patient-derived cancer cell lines, for instance, colorectal, breast, prostate, and pancreatic cancer [24]. These resistant cell lines were established by exposing chemotherapy-sensitive cells to gradually increasing concentrations of chemotherapy over a period of 8-10 months [25].…”