Abstract 2058: Systematic evaluation of drug combinations in vitro and in vivo.
Authors: Wiesmann Marion , Stump Mark , Caponigro Giordano , Duhl David , Firestone Brant , Gesner Tom , Gruenenfelder Bjoern , Guthy Daniel Alexander , Holash Jocelyn , King Fred , Lehar Joseph , Leroy Christophe , Liu Manway , Petruzelli Lilli , Porter Dale , McSheehy Paul , Menezes Daniel , Reddy Anupama , Roesel Johannes , Schnell Christian , Smith Timothy R. , Wartmann Markus 
Published: August 2014

In recent years great advances have been made in developing targeted cancer therapeutics that produce dramatic responses in a subset of rationally selected patients. The initial breakthrough of the targeted design concept was established by the treatment of chronic myelogenous leukemia with Abl inhibitors and has been expanded to other cancer indications. As a consequence of this early success in CML, the identification and targeting of genetic lesions that confer cancer dependence has become an established strategy for drug discovery efforts. However, this approach has met with mixed degrees of success as confounding factors, such as tumor heterogeneity, have often resulted in partial responses and/or the emergence of resistance when targeted therapies were employed as single agents.

To improve the therapeutic benefit in cancer, rationally-devised novel combinations of two or more agents are being explored clinically. To discover combinations that may be more effective therapies, an unbiased, systematic approach was used to identify drug combinations in vitro, using a panel of genetically diverse, and well characterized cell lines from the cancer cell line encyclopedia (CCLE: Barretina et al. Nature 2012). For three cancer indications, all pairwise combinations of 18 selected drugs (both novel inhibitors and standards of care) were tested as dose matrices in a proliferation assay. Synergistic interactions were scored using isobologram/Loewe's excess inhibition and synergistic concentration ranges for each agent were identified. However, the clinical translation of positive combinations from in vitro matrix-based screens into clinically-relevant doses and schedules are challenging, due to host biology, tumor-stroma interactions, and the pharmacokinetic and pharmacodynamics of drug delivery. To explore this higher complexity, we evaluated the in vitro to in vivo translation of drug synergies in immune-compromised mouse tumor xenograft models. To recapitulate the pharmacological combination effects in vivo, mouse pharmacokinetic data and simulation was used to determine single agent doses that would result in the desired compound plasma concentration range and duration of action. Pharmakokinetics, pharmacodynamics, antitumor activity and tolerability of the combinations were then tested in tumor-bearing mice. Observed combination effects in vivo could in some cases be explained by either the expected biological pathway interactions or partially by physiological effects relating to drug-drug interactions.

Citation Format: Marion Wiesmann, Mark Stump, Giordano Caponigro, David Duhl, Brant Firestone, Tom Gesner, Bjoern Gruenenfelder, Daniel Alexander Guthy, Jocelyn Holash, Fred King, Joseph Lehar, Christophe Leroy, Manway Liu, Lilli Petruzelli, Dale Porter, Paul McSheehy, Daniel Menezes, Anupama Reddy, Johannes Roesel, Christian Schnell, Timothy R. Smith, Markus Wartmann. Systematic evaluation of drug combinations in vitro and in vivo. [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 2058. doi:10.1158/1538-7445.AM2013-2058