38 Abbreviations: BC = breast cancer; BH3 = pro-apoptotic member of the Bcl-2 protein family; anti-CTLA4 mAb = anti–cytotoxic T-lymphocyte associated protein 4 monoclonal antibody; CDK = cyclin-dependent kinase; DNA = deoxyribonucleic acid; EFGR, ERB = another term for ErbB, the epidermal growth factor receptor protein family; HDAC = histone deacetylase; HGF/c-Met = hepatocyte growth factor/MET proto-oncogene, receptor tyrosine kinase; JAK = Janus kinase family; MBC = metastatic breast cancer; Notch = family of proteins involved in intracellular signaling; PARP = poly-ADP ribose polymerase; PTEN = phosphatase and tensin homolog; RAF/MEK/ERK/ALK = a key cellular signaling pathway; TGF-b = transforming growth factor beta; VEGF = vascular endothelial growth factor. DEREGULATING CELLULAR ENERGETICS DIG-HIF1 being studied in early BC. Phase II RESISTING CELL DEATH IAP (inhibit apoptosis proteins) (LCL161) GENOME INSTABILITY AND MUTATION PARP inhibitors HDAC inhibitors* Minor groove of DNA inhibitor (PM01183) SUSTAINING PROLIFERATIVE SIGNALING PI3/Akt/mTOR Hormone-mediated JAK PTEN Notch RAF/MEK/ERK/ALK ERB receptors Other EVADING GROWTH SUPPRESSORS CDK inhibitors Agents: Palbociclib LEE011 Y2835219 AVOIDING IMMUNE DESTRUCTION 18 vaccine 7 immunomodulators ENABLING REPLICATIVE IMMORTALITY GRN163L trial halted in MBC in 2013 Other telomerase inhibitors in trials for hematologic cancers TUMOR- PROMOTING INFLAMMATION Inflammation remains of key interest in BC ACTIVATING INVASION AND METASTASIS TGF-b inhibitor (fresolimumab) INDUCING ANGIOGENESIS VEGF inhibitors ACTIVE CLINICAL TRIAL DETAILS Note: 37 additional trials not targeted or could not be assigned to a hallmark SUSTAINING PROLIFERATIVE SIGNALING EVADING GROWTH SUPPRESSORS AVO ID I N G I M M U N E D E S T R U C T I O N E N A B L I N G R E P L I C A T I V E I M M O R T A L I T Y T U M O R - P R O M O T I N G I N F L A M M A T I O N A C T I V A T I N G I N V A S I O N & M E T A S T A S I S I N D U C I N G A N G I O G E N E S I S G E N O M E I N S T A B I L I T Y A N D M U T A T I O N R E S I S T I N G C E L L D E A T H D E R E G U L A T I N G C E L L U L A R E N ERG ETICS 95 9 27 0 0 1 25 0 4 1 Active MBC Clinical Trials Categorized by the Hallmarks of Cancer: The Next Generation *does not relate to "Genome Instability and Mutation" hallmark but instead is a modulator of transcription that is not easily fit into any one of the hallmark categories. Figure 3: 162 MBC Clinical Trials Assigned to the Hallmarks of Cancer Framework