title: Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation.
abstract: The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies.Cancer Res; 77(11); 2869-80. ©2017 AACR.
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Frazier
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Bertout
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: William S
authors.initials: WS
authors.lastname: Kerwin
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Alicia
authors.initials: A
authors.lastname: Moreno-Gonzalez
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Joey R
authors.initials: JR
authors.lastname: Casalini
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Grenley
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Emily
authors.initials: E
authors.lastname: Beirne
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Kori L
authors.initials: KL
authors.lastname: Watts
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Andy
authors.initials: A
authors.lastname: Keener
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Thirstrup
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Ilona
authors.initials: I
authors.lastname: Tretyak
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington.
authors.forename: Sally H
authors.initials: SH
authors.lastname: Ditzler
authors.affiliation: Veterinary Cancer Specialty Care, Lynnwood, Washington.
authors.forename: Chelsea D
authors.initials: CD
authors.lastname: Tripp
authors.affiliation: Oncology Department, Seattle Veterinary Specialists, Kirkland, Washington.
authors.forename: Kevin
authors.initials: K
authors.lastname: Choy
authors.affiliation: Oncology Department, Summit Veterinary Referral Center, Tacoma, Washington.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gillings
authors.affiliation: Oncology Department, BluePearl Veterinary Partners, Renton, Washington.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Breit
authors.affiliation: Oncology Department, BluePearl Veterinary Partners, Seattle, Washington.
authors.forename: Karri A
authors.initials: KA
authors.lastname: Meleo
authors.affiliation: Oncology Department, Summit Veterinary Referral Center, Tacoma, Washington.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rizzo
authors.affiliation: Oncology Department, BluePearl Veterinary Partners, Seattle, Washington.
authors.forename: Chamisa L
authors.initials: CL
authors.lastname: Herrera
authors.affiliation: Oncology Department, Seattle Veterinary Specialists, Seattle, Washington.
authors.forename: James A
authors.initials: JA
authors.lastname: Perry
authors.affiliation: Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Seattle Children's Hospital and Regional Medical Center, Seattle, Washington.
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.affiliation: Presage Biosciences, Inc., Seattle, Washington. rich.klinghoffer@presagebio.com.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Klinghoffer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004285:Dogs; D018432:Drug Resistance, Multiple; D006801:Humans; D056747:Immunomodulation / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy*; D057285:Precision Medicine / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents