title: The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma.
abstract: Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma.
authors: Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors: Chanh
authors: C
authors: Huynh
authors: Laura
authors: L
authors: Poliseno
authors: Miguel F
authors: MF
authors: Segura
authors: Ratna
authors: R
authors: Medicherla
authors: Adele
authors: A
authors: Haimovic
authors: Silvia
authors: S
authors: Menendez
authors: Shulian
authors: S
authors: Shang
authors: Anna
authors: A
authors: Pavlick
authors: Yongzhao
authors: Y
authors: Shao
authors: Farbod
authors: F
authors: Darvishian
authors: John F
authors: JF
authors: Boylan
authors: Iman
authors: I
authors: Osman
authors: Eva
authors: E
authors: Hernando
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines; D051880:Receptors, Notch; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons