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A technology platform to assess multiple cancer agents simultaneously within a patient's tumor.
Klinghoffer, Richard A; Bahrami, S Bahram; Hatton, Beryl A; Frazier, Jason P; Moreno-Gonzalez, Alicia; Strand, Andrew D; Kerwin, William S; Casalini, Joseph R; Thirstrup, Derek J; You, Sheng; Morris, Shelli M; Watts, Korashon L; Veiseh, Mandana; Grenley, Marc O; Tretyak, Ilona; Dey, Joyoti; Carleton, Michael; Beirne, Emily; Pedro, Kyle D; Ditzler, Sally H; Girard, Emily J; Deckwerth, Thomas L; Bertout, Jessica A; Meleo, Karri A; Filvaroff, Ellen H; Chopra, Rajesh; Press, Oliver W; Olson, James M.
Afiliação
  • Klinghoffer RA; Presage Biosciences, Seattle, WA 98109, USA.
  • Bahrami SB; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Hatton BA; Presage Biosciences, Seattle, WA 98109, USA.
  • Frazier JP; Presage Biosciences, Seattle, WA 98109, USA.
  • Moreno-Gonzalez A; Presage Biosciences, Seattle, WA 98109, USA.
  • Strand AD; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Kerwin WS; Presage Biosciences, Seattle, WA 98109, USA.
  • Casalini JR; Presage Biosciences, Seattle, WA 98109, USA.
  • Thirstrup DJ; Presage Biosciences, Seattle, WA 98109, USA.
  • You S; Presage Biosciences, Seattle, WA 98109, USA.
  • Morris SM; Presage Biosciences, Seattle, WA 98109, USA.
  • Watts KL; Presage Biosciences, Seattle, WA 98109, USA.
  • Veiseh M; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Grenley MO; Presage Biosciences, Seattle, WA 98109, USA.
  • Tretyak I; Presage Biosciences, Seattle, WA 98109, USA.
  • Dey J; Presage Biosciences, Seattle, WA 98109, USA.
  • Carleton M; Presage Biosciences, Seattle, WA 98109, USA.
  • Beirne E; Presage Biosciences, Seattle, WA 98109, USA.
  • Pedro KD; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Ditzler SH; Presage Biosciences, Seattle, WA 98109, USA.
  • Girard EJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Deckwerth TL; Presage Biosciences, Seattle, WA 98109, USA.
  • Bertout JA; Presage Biosciences, Seattle, WA 98109, USA.
  • Meleo KA; Oncology Department, BluePearl Veterinary Partners, Seattle, WA 98125, USA.
  • Filvaroff EH; Celgene Corporation, San Francisco, CA 94158, USA.
  • Chopra R; Celgene Corporation, Summit, NJ 07901, USA.
  • Press OW; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Olson JM; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Sci Transl Med ; 7(284): 284ra58, 2015 Apr 22.
Article em En | MEDLINE | ID: mdl-25904742
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ensaios de Seleção de Medicamentos Antitumorais / Linfoma / Neoplasias / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Sci Transl Med Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ensaios de Seleção de Medicamentos Antitumorais / Linfoma / Neoplasias / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Sci Transl Med Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos
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