title: A technology platform to assess multiple cancer agents simultaneously within a patient's tumor.
abstract: A fundamental problem in cancer drug development is that antitumor efficacy in preclinical cancer models does not translate faithfully to patient outcomes. Much of early cancer drug discovery is performed under in vitro conditions in cell-based models that poorly represent actual malignancies. To address this inconsistency, we have developed a technology platform called CIVO, which enables simultaneous assessment of up to eight drugs or drug combinations within a single solid tumor in vivo. The platform is currently designed for use in animal models of cancer and patients with superficial tumors but can be modified for investigation of deeper-seated malignancies. In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of action of each drug. The observed localized responses predicted responses to systemically delivered drugs in animals. In pair-matched lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine and an unexpected enhanced sensitivity to mafosfamide in multidrug-resistant lymphomas compared with chemotherapy-naïve lymphomas. A CIVO-enabled in vivo screen of 97 approved oncology agents revealed a novel mTOR (mammalian target of rapamycin) pathway inhibitor that exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors. Finally, feasibility studies to assess the use of CIVO in human and canine patients demonstrated that microinjection of drugs is toxicity-sparing while inducing robust, easily tracked, drug-specific responses in autochthonous tumors, setting the stage for further application of this technology in clinical trials.
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Klinghoffer
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: S Bahram
authors.initials: SB
authors.lastname: Bahrami
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Beryl A
authors.initials: BA
authors.lastname: Hatton
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Frazier
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Moreno-Gonzalez
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Strand
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Kerwin
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casalini
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Thirstrup
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: You
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Shelli M
authors.initials: SM
authors.lastname: Morris
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Korashon L
authors.initials: KL
authors.lastname: Watts
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Mandana
authors.initials: M
authors.lastname: Veiseh
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Grenley
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Tretyak
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Joyoti
authors.initials: J
authors.lastname: Dey
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Carleton
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Beirne
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Pedro
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Sally H
authors.initials: SH
authors.lastname: Ditzler
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Girard
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Deckwerth
authors.affiliation: Presage Biosciences, Seattle, WA 98109, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Bertout
authors.affiliation: Oncology Department, BluePearl Veterinary Partners, Seattle, WA 98125, USA.
authors.forename: Karri A
authors.initials: KA
authors.lastname: Meleo
authors.affiliation: Celgene Corporation, San Francisco, CA 94158, USA.
authors.forename: Ellen H
authors.initials: EH
authors.lastname: Filvaroff
authors.affiliation: Celgene Corporation, Summit, NJ 07901, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.|Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.|Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D015415:Biomarkers; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000737:chemistry; D004285:Dogs; D004317:Doxorubicin / Q000737:chemistry; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D011239:Prednisolone / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014750:Vincristine / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C048341:mafosfamide; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases