Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation.

Autor:	Frazier JP; Presage Biosciences, Inc., Seattle, Washington., Bertout JA; Presage Biosciences, Inc., Seattle, Washington., Kerwin WS; Presage Biosciences, Inc., Seattle, Washington., Moreno-Gonzalez A; Presage Biosciences, Inc., Seattle, Washington., Casalini JR; Presage Biosciences, Inc., Seattle, Washington., Grenley MO; Presage Biosciences, Inc., Seattle, Washington., Beirne E; Presage Biosciences, Inc., Seattle, Washington., Watts KL; Presage Biosciences, Inc., Seattle, Washington., Keener A; Presage Biosciences, Inc., Seattle, Washington., Thirstrup DJ; Presage Biosciences, Inc., Seattle, Washington., Tretyak I; Presage Biosciences, Inc., Seattle, Washington., Ditzler SH; Presage Biosciences, Inc., Seattle, Washington., Tripp CD; Veterinary Cancer Specialty Care, Lynnwood, Washington., Choy K; Oncology Department, Seattle Veterinary Specialists, Kirkland, Washington., Gillings S; Oncology Department, Summit Veterinary Referral Center, Tacoma, Washington., Breit MN; Oncology Department, BluePearl Veterinary Partners, Renton, Washington., Meleo KA; Oncology Department, BluePearl Veterinary Partners, Seattle, Washington., Rizzo V; Oncology Department, Summit Veterinary Referral Center, Tacoma, Washington., Herrera CL; Oncology Department, BluePearl Veterinary Partners, Seattle, Washington., Perry JA; Oncology Department, Seattle Veterinary Specialists, Seattle, Washington., Amaravadi RK; Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Olson JM; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Seattle Children's Hospital and Regional Medical Center, Seattle, Washington., Klinghoffer RA; Presage Biosciences, Inc., Seattle, Washington. rich.klinghoffer@presagebio.com.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2017 Jun 01; Vol. 77 (11), pp. 2869-2880. Date of Electronic Publication: 2017 Mar 31.
DOI:	10.1158/0008-5472.CAN-17-0084
Abstrakt:	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 . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu