title: A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.
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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Medical Science Training Program, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Melodi Javid
authors.initials: MJ
authors.lastname: Whitley
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Cardona
authors.affiliation: School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Lazarides
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. PK/PD Core Laboratory, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.affiliation: Lumicell Inc., Wellesley, MA 02481, USA.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Ferrer
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Cahill
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Chang-Lung
authors.initials: CL
authors.lastname: Lee
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Blazer
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: E Shelley
authors.initials: ES
authors.lastname: Hwang
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Greenup
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Mosca
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Medical Science Training Program, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Mito
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Cuneo
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Larrier
authors.affiliation: Duke Translational Medicine Institute, Regulatory Affairs Group, Duke University Medical Center, NC 27710, USA.
authors.forename: Erin K
authors.initials: EK
authors.lastname: O'Reilly
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Riedel
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Eward
authors.affiliation: Lumicell Inc., Wellesley, MA 02481, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Strasfeld
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Lumicell Inc., Wellesley, MA 02481, USA.
authors.forename: W David
authors.initials: WD
authors.lastname: Lee
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Linda G
authors.initials: LG
authors.lastname: Griffith
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Moungi G
authors.initials: MG
authors.lastname: Bawendi
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA. david.kirsch@duke.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Brigman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis; D003952:Diagnostic Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007275:Injections, Intravenous; D055442:Metabolome; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis*; D010447:Peptide Hydrolases / Q000378:metabolism*; D012509:Sarcoma / Q000175:diagnosis; D014018:Tissue Distribution
chemical_list: D005456:Fluorescent Dyes; D010447:Peptide Hydrolases