title: High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097.
abstract: Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the γ-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation.
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc. Nutley, NJ 07110, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Luistro
authors.forename: Daisy
authors.initials: D
authors.lastname: Carvajal
authors.forename: Melissa
authors.initials: M
authors.lastname: Smith
authors.forename: Tom
authors.initials: T
authors.lastname: Nevins
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yin
authors.forename: James
authors.initials: J
authors.lastname: Cai
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Christine
authors.initials: C
authors.lastname: Rizzo
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: David
authors.initials: D
authors.lastname: Heimbrook
authors.forename: John F
authors.initials: JF
authors.lastname: Boylan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D016209:Interleukin-8 / Q000097:blood / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001552:Benzazepines; D015850:Interleukin-6; D016209:Interleukin-8; 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