Abstract 4497: Design and synthesis of hybrid drugs to target inflammatory pathways in breast cancer
Authors: Kastrati Irida , Siklos Marton , Litosh Vladislav , Thatcher Gregory , Frasor Jonna 
Published: August 2015

Abstract
In breast tumors, activation of the nuclear factor κB (NFκB) and cyclooxygenase (COX)-prostaglandin pathways promote cell survival, migration, invasion, angiogenesis, and resistance to therapy - all phenotypes of aggressive disease where therapy options remain limited. Thus, adding an anti-inflammatory agent to breast cancer treatment would be beneficial but no such drugs have been approved, either as mono- or adjuvant therapy. Moreover, redundancy and interdependence between inflammatory signaling implies that blocking one pathway is unlikely to be effective. We rationalized that targeting of multiple inflammatory pathways can be achieved via a hybrid drug, which, by definition, is a chemical entity capable of interacting simultaneously with multiple targets. Hence, hybrid drugs consisting of clinically relevant moieties aimed at multiple inflammatory pathways were synthesized and tested.
To target the NFκB pathway, we utilized dimethyl fumarate (DMF), a safe and effective anti-inflammatory drug already in clinical use. For the first time, we show that DMF effectively blocks NFκB activity in breast cancer cells. To target the COX2-PGE2 axis in breast cancer cells, we selected the classical NSAID aspirin (ASA), given its beneficial effect in reducing breast cancer incidence with extended ASA use. Our first hybrid drug, GTCpFE, consists of DMF linked to ASA. We find that GTCpFE inhibits NFκB activity as does DMF, while retaining its ASA-like activity. GTCpFE blocks p65 nuclear entry like DMF but, in addition, also inhibits key kinases (IKKα/β) in the NFκB pathway. This suggests that GTCpFE as a hybrid drug has gained new activities over parental DMF or ASA. GTCpFE inhibits breast cancer stem cells, an important NFκB- and PGE2-dependent phenotype in aggressive cancers, more effectively than ASA, DMF, or the combination of the two. Thus, as a proof-of-principle, the hybrid drug GTCpFE shows increased efficacy and potency by modulating multiple inflammatory pathways.
Because an anti-inflammatory therapy is not cytocidal on its own on the bulk of the tumor, we decided to combine DMF with more conventional therapies. Given that majority of breast cancers express estrogen receptor (ER), our second hybrid drug, Ral-Fum, consists of DMF linked to Raloxifene (Ral), a selective ER-modulator, to specifically target ER+ breast cancers. This hybrid drug shows improved anti-NFκB activity over DMF while maintaining ER antagonism, hence is both an endocrine therapy and an anti-inflammatory agent. Moreover, Ral-Fum attenuates the formation of endocrine resistant colonies. Taken together, our results indicate that a hybrid drug strategy to target essential factors for breast cancer cell proliferation and survival, such as ER, and multiple aspects of inflammation can generate promising and novel therapeutic agents to treat aggressive breast cancers.
Citation Format: Irida Kastrati, Marton Siklos, Vladislav Litosh, Gregory Thatcher, Jonna Frasor. Design and synthesis of hybrid drugs to target inflammatory pathways in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4497. doi:10.1158/1538-7445.AM2015-4497