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      A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer

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          Abstract

          Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

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          Author and article information

          Journal
          101505086
          36963
          Sci Transl Med
          Sci Transl Med
          Science translational medicine
          1946-6234
          1946-6242
          8 March 2016
          6 January 2016
          06 January 2017
          : 8
          : 320
          : 320ra4
          Affiliations
          [1 ]Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
          [2 ]Medical Science Training Program, Duke University Medical Center, Durham, NC 27710, USA
          [3 ]Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
          [4 ]School of Medicine, Duke University Medical Center, Durham, NC 27710, USA
          [5 ]Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
          [6 ]PK/PD Core Laboratory, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
          [7 ]Lumicell Inc., Wellesley, MA 02481, USA
          [8 ]Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
          [9 ]Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
          [10 ]Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
          [11 ]Duke Translational Medicine Institute, Regulatory Affairs Group, Duke University Medical Center, NC 27710, USA
          [12 ]Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA
          [13 ]Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
          [14 ]Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
          Author notes
          []Corresponding author. david.kirsch@ 123456duke.edu
          [*]

          Present address: Department of Pathology, NYU Langone Medical Center, New York, NY 10016, USA.

          Co-senior authors.

          Article
          PMC4794335 PMC4794335 4794335 nihpa765770
          10.1126/scitranslmed.aad0293
          4794335
          26738797
          9ece7617-c490-4963-9575-ffe49bf663ab
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