K-8669) with dalotuzumab (mk-0646) Fgf Dovitinib (TKI258)mTOR inhibitor and IGF-1R mABNCTTKI inhibits Phase FGFR1?, VEGFR Phase / and PDGFRDovitinib (TKI258)Dovitinib (TKI258)Azd4547 AzdDovitinib monotherapy, four groups of MBC pts: (group Dovitinib has activity stratified by FGF 1: FGFR1+, HR+), (group in breast cancers with amplification 2: FGFR1+, HR-) (group 3: amplified FGF pathway FGFR1-, HR+), (group 4: FGFR1-, HR-) TKI inhibits Dovitinib(TKI258) + AI ER+/HER2- postmenopausal FGFR1?, VEGFR MBC resistant to AI with and PDGFR fgfr1 amplification status confirmed TKI inhibits Phase Fulvestrant +/Postmenopausal pts with FGFR1?, VEGFR randomized Dovitinib,stratified by HER2-/HR+ LA BC or MBC and PDGFR FGF progressing inside 12 mos of completion of adjuvant endocrine therapy or just after 1 prior endocrine therapy in the advanced setting Phase amplification HER2-MBC with fgfr1 amplification Phase Fulvestrant +/ER+ postmenopausal LABC AZD4547 or MBC with fgfr1 polysomy or gene amplification resistant to endocrine therapy (Adjuvant or Firstline Metastatic)[94]NCTNCTNCT01795768 NCTTargeting cell cycle regulators Pd 0332991 CDK4/6 inhibitor Phase / Letrozole +/- PD randomized 0332991 Pd-0332991 (palbociclib) Lee011 Epigenetic therapy Vorinostat CDK4/6 inhibitor Phase Letrozole +/- PD randomized 0332991 Phase b/ LEE011 + exemestane +/-everolimusFirst line therapy for postmenopausal pts with ER+/HER2- MBC Initially line therapy for postmenopausal pts with ER+/HER2- MBC Postmenopausal pts with ER+/HER2- LABC/MBC[99]NCTNCTHDAC inhibitorEntinostatHDAC inhibitorPanobinostat VorinostatHDAC inhibitor HDAC inhibitorVorinostatN = 43; 34 evaluable, 7 [105] (21 ) PR; 4 (29 ) SD; ORR 19 , CBR 40 phase Exmestane+/- entinostat MBC or LA BC pts who N = 130; PFS: 4.898552-72-2 manufacturer 3 vs two.2-Bromo-5-cyclopropylpyrazine site 3 mo [106] randomized had progressed on prior ( HR 0.PMID:25955218 73, 95 CI: 0.50 to nonsteroidal AI 1.07; P = 0.06); OS: 28.1 vs 19.8 mo (HR 0.59, CI, 0.36 to 0.97; P = .036), favoring mixture Phase / Panobinostat + letrozole MBC, triple negative phase II NCT01105312 portion phase Vorinostat + AI ER + MBC pts who NCT01153672 previously derived advantage from AI phase Vorinostat/placebo Principal operable breast Ongoing NCT00616967 + nab-paclitaxel + cancer, triple-negative or carboplatin (n = 62) higher grade ER-positive, HER2-negative Phase Vorinostat + tamoxifen ER+ MBC progressed on earlier endocrine therapyMBC: Metastatic BC; LABC: Locally advanced BC; mAB: monoclonal antibody; ORR: Objective response price; CBR: Clinical benefit rate response or stable illness 24 wk; PR: Partial response; SD: Stable illness; TKI: Tyrosine Kinase Inhibitor; PI3K/AKT/mTOR: PI3K-AKT- mammalian target of rapamycin (mTOR) pathway; IGF1R: Insulin-like development factor-1 receptor pathway; FGF: Fibroblast growth element. signaling.and plays a important role in embryonic development. TheHh pathway has been increasingly recognized as playingWJCO|wjgnetAugust ten, 2014|Volume five|Situation three|Zhao M et al . Advances in endocrine-resistant breast cancera essential part in carcinogenesis in the final decade. 3 mammalian Hh ligands have already been identified in humans, as denoted by the prefixes Sonic, Indian, and Desert (SHH, IHH, and DHH). They activate the Hh signaling pathway by binding for the cell surface receptor Patched (PTCH), which otherwise represses the activity on the transmembrane receptor like protein Smoothened (SMO). Release of SMO from PTCH-mediated repression subsequently results in the modulation of GLI (gliomaassociated oncoge.