Abstract 4543: High-throughput combination screening identifies novel drug-drug pairings for a Bruton's tyrosine kinase inhibitor against the ABC subtype of diffuse large B-cell lymphomas.
Authors: Mathews Lesley A. , Guha Rajarshi , Shinn Paul , Young Ryan M. , Lim Kian-Huat , Keller Jonathan , Liu Dongbo , Yasgar Adam , McKnight Crystal , Boxer Matthew B. , Duveau Damien Y. , Jiang Jian-kang , Michael Sam , Mott Bryan T. , Patel Paresma R. , Leister William , Maloney David J. , LeClair Christopher A. , Rai Ganesha , Jadhav Ajit , Peyser Brian D. , Austin Christopher P. , Martin Scott , Simeonov Anton , Ferrer Marc , Staudt Louis , Thomas Craig J. 
Published: August 2014

Abstract
The vast majority of cancer treatments currently administered to patients consist of combinations of more than one drug via routine infusions that adhere to specific dosing schedules. It is thought that this multi-arm and time dependent approach will kill not only the tumor cells within the primary site, but also any metastatic lesions, and importantly, any circulating tumor cells (CTCs) which may still exist in the blood. Combination therapies have also been developed as a means to reduce general cytotoxic side effects and prevent resistance and recurrence. Our labs have recently developed a high throughput screening platform to test compounds in pair-wise combinations to rapidly and systematically identify additive, synergistic and antagonistic drug combinations. This HTS capability can easily generate hundreds of dose response matrices in a single study and can increase significantly when applied to multiple cell lines. We are using this combination screening platform with in vitro models from both established cell lines and primary patient material, and we expect it will serve as a very valuable tool and a starting point when designing clinical trials after these combinations show promise within in vivo models. In a proof of concept study, we tested combinations of compounds that effectively kill 2 established lines of the ABC sub-type of diffuse large B-cell lymphoma (DLBCL); TMD8 and HBL1. We will present the infrastructure and methods that we have developed to implement the combination screens, visualize data from the combination dose response comparisons and numerically compare combinations in terms of their response matrices. We will also describe how this approach allows us to investigate putative polypharmacological effects that play a role in compound combination responses. Finally, we will show the results of a combination screen with TMD8 and HBL1 cells, including the identification of a novel drug-drug combination for the BTK inhibitor ibrutinib (PCI-32765) which is of both basic and translational interest for the treatment of DLBCL.
Citation Format: Lesley A. Mathews, Rajarshi Guha, Paul Shinn, Ryan M. Young, Kian-Huat Lim, Jonathan Keller, Dongbo Liu, Adam Yasgar, Crystal McKnight, Matthew B. Boxer, Damien Y. Duveau, Jian-kang Jiang, Sam Michael, Bryan T. Mott, Paresma R. Patel, William Leister, David J. Maloney, Christopher A. LeClair, Ganesha Rai, Ajit Jadhav, Brian D. Peyser, Christopher P. Austin, Scott Martin, Anton Simeonov, Marc Ferrer, Louis Staudt, Craig J. Thomas. High-throughput combination screening identifies novel drug-drug pairings for a Bruton's tyrosine kinase inhibitor against the ABC subtype of diffuse large B-cell lymphomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4543. doi:10.1158/1538-7445.AM2013-4543