Abstract P6-10-06: Rational combination therapy against triple-negative breast cancer

Abstract

Abstract Background: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with higher incidence of recurrence, more distant metastasis, and poorer survival. This subtype is also characterized by complex genomes where little of their genomes remain at normal copy number but without high, focal copy number amplifications. At the transciptome level, the majority of TNBC (∼75%) are classified as basal-like breast cancer (BLBC) according to the five intrinsic subtypes. Despite considerable genomic and gene expression characterization of TNBC, proteomic and phospho-proteomic investigations of this disease are limited with no available targeted therapies in clinical use. Methods & Results: We used the Kinex™ antibody array (http://www.kinexus.ca/) to interrogate protein/phosphoproteins levels in 43 primary breast cancer biopsies (16 TNBC, 16 ER/PR positive and 11 HER2-positive) and 16 breast cancer cell lines. Unsupervised hierarchical clustering of protein/phosphoprotein levels revealed two subgroups of TNBC in comparison to other subtypes. Western blotting and Proteome Profiler™ Arrays (R&D Systems) were used to validate deregulated proteins/phosphoproteins in TNBC. Pathway analysis revealed that one subgroup of TNBC exploits overlapping and cross-talking networks for survival. These signaling networks are downstream from elevated activation of EGFR, integrins and Insulin-like growth factor 1 receptor (IGF1R). Targeted molecular inhibitors of activated kinases in these pathways showed specificity against basal-like/TNBC cell lines compared to other subtypes in vitro. These activated kinases/networks represent druggable targets for the treatment of TNBC but may be limited by compensatory effect of the complex cross-talking signaling networks. To overcome compensatory downstream signaling that would limit the inhibition of a given pathway; we developed EGFR-targeted radioimmunotherapy (RIT) strategy to systemically deliver cytotoxic loads of beta particles (177Lu) that would kill targeted cells and surrounding cells by crossfire effect. The combination of EGFR-directed RIT with chemotherapy and PARP inhibition successfully treated orthotopic and metastatic TNBC models established from cell lines and patient-derived xenografts. The superior efficacy of this triple-agent combination therapy is explained by enhanced DNA damage and reduced DNA repair response, higher apoptotic cell death and the elimination of putative breast cancer stem cells. Conclusion: Proteomic analysis of TNBC provides a powerful tool to elucidate druggable signaling networks with therapeutic potential. TNBC utilizes complex interacting signaling networks and rational combination therapies are required for effective therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-06.