title: A Platform for Rapid, Quantitative Assessment of Multiple Drug Combinations Simultaneously in Solid Tumors In Vivo.
abstract: While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies.
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Joyoti
authors.initials: J
authors.lastname: Dey
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Kerwin
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Grenley
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casalini
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Ilona
authors.initials: I
authors.lastname: Tretyak
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Sally H
authors.initials: SH
authors.lastname: Ditzler
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Thirstrup
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Frazier
authors.affiliation: Celgene Corporation, San Francisco, California, United States of America.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Pierce
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Carleton
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Klinghoffer
mesh_terms: D000068196:Albumin-Bound Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000814:Aniline Compounds; D013449:Sulfonamides; C528561:navitoclax