title: Selective small molecule Stat3 inhibitor reduces breast cancer tumor-initiating cells and improves recurrence free survival in a human-xenograft model.
abstract: Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24-/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24-/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors.
authors.affiliation: The Methodist Cancer Center, Houston, Texas, United States of America.
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Dave
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Landis
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.forename: Lacey E
authors.initials: LE
authors.lastname: Dobrolecki
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Westbrook
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology* / Q000627:therapeutic use; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; D043823:Taxoids; D000077143:Docetaxel