title: Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells.
abstract: Recent evidence suggests that Notch signaling may play a role in regulation of cancer stem cell (CSC) self-renewal and differentiation hence presenting a promising target for development of novel therapies for aggressive cancers such as triple negative breast cancer (TNBC). We generated Notch1 monoclonal antibodies (mAbs) that specifically bind to the negative regulatory region of human Notch1. Notch1 inhibition in TNBC Sum149 and patient derived xenograft (PDX) 144580 models led to significant TGI particularly in combination with docetaxel. More interestingly, Notch1 mAbs caused a reduction in mammosphere formation and CD44+/CD24-/lo cell population. It also resulted in decreased tumor incidence upon re-implantation and delay in tumor recurrence. Our data demonstrated a potent antitumor efficacy of Notch1 mAbs, with a remarkable activity against CSCs. These findings suggest that anti-Notch1 mAbs may provide novel therapies to improve the efficacy of conventional therapies by directly targeting the CSC niche. They may also delay tumor recurrence and hence have a major impact on cancer patient survival.
authors.affiliation: Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, La Jolla, CA 92121, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Qiu
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Peng
authors.forename: Ivy
authors.initials: I
authors.lastname: Jiang
authors.forename: Christopher
authors.initials: C
authors.lastname: Carroll
authors.forename: Guangzhou
authors.initials: G
authors.lastname: Han
authors.forename: Isha
authors.initials: I
authors.lastname: Rymer
authors.forename: John
authors.initials: J
authors.lastname: Lippincott
authors.forename: Joseph
authors.initials: J
authors.lastname: Zachwieja
authors.forename: Ketan
authors.initials: K
authors.lastname: Gajiwala
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kraynov
authors.forename: Stephane
authors.initials: S
authors.lastname: Thibault
authors.forename: Donna
authors.initials: D
authors.lastname: Stone
authors.forename: Yijie
authors.initials: Y
authors.lastname: Gao
authors.forename: Susan
authors.initials: S
authors.lastname: Sofia
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallo
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yang
authors.forename: Kang
authors.initials: K
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects*; D018874:Spheroids, Cellular / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051881:Receptor, Notch1; D043823:Taxoids; D000077143:Docetaxel