The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer
Open accessAbstract
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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“and identification of residual cancer after surgery in humans through a protease-activated fluorescent probe.91”
From Early detection of pancreatic cancer (2020) · cites this paper as [91]
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Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus
Srinivas, S., Watanabe, T., Lin, C.-S., William, C. M., Tanabe, Y., Jessell, T. M., & Costantini, F. (2001) · BMC Developmental Biology · doi:10.1186/1471-213x-1-4 · Cited by 3,121 · cited 1×
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MethodDistinct role of macrophages in different tumor microenvironments
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“The labeling of tumor-associated macrophages likely occurs because these cells also express high levels of proteases (24), and the intraoperative identification and removal of these cells may, in fact, be beneficial to patients because these cells are associated with tumor progression and metastasis (25, 26).”
BackgroundPower and sample size calculations
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“Sample sizes were selected before initiating the study based on previous intraoperative imaging studies conducted in the laboratory (17), and power calculations were performed as described previously (30).”
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Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy
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“The labeling of tumor-associated macrophages likely occurs because these cells also express high levels of proteases (24), and the intraoperative identification and removal of these cells may, in fact, be beneficial to patients because these cells are associated with tumor progression and metastasis (25, 26).”
BackgroundIn vivo imaging of tumors with protease-activated near-infrared fluorescent probes
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“Protease-activated probes may provide increased tumor to normal contrast as they are designed to be optically inactive until cleaved by proteases that are highly expressed in tumors, like cathepsin proteases and matrix metalloproteases (MMPs) (13, 22-24).”
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“Although radiation therapy significantly improves local recurrence-free survival for the entire population (1-4), the majority of patients, who would have achieved local control with surgery alone, derive no benefit from adjuvant radiation therapy.”
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Research works printed but not linked: 1
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Metadata
- Authors
- Whitley, M. J., Cardona, D. M., Lazarides, A. L., Spasojevic, I., Ferrer, J. M., Cahill, J., Lee, C.-L., Snuderl, M., Blazer, D. G., Hwang, E. S., Greenup, R. A., Mosca, P. J., Mito, J. K., Cuneo, K. C., Larrier, N. A., O’Reilly, E. K., Riedel, R. F., Eward, W. C., Strasfeld, D. B., Fukumura, D., Jain, R. K., Lee, W. D., Griffith, L. G., Bawendi, M. G., Kirsch, D. G., & Brigman, B. E.
- Affiliations
- Duke Medical Center (US)
- Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
- Lumicell (United States) (US)
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Kirsch, David G.
- Brigman, Brian E.
- ORCID
- Whitley, Melodi Javid
- Cardona, Diana M.
- Lazarides, Alexander L.
- Lee, Chang-Lung
- Snuderl, Matija
- Blazer, Dan G.
- Hwang, E. Shelley
- Greenup, Rachel A.
- Mosca, Paul J.
- Mito, Jeffrey K.
- Cuneo, Kyle C.
- O’Reilly, Erin K.
- Riedel, Richard F.
- Eward, William C.
- Fukumura, Dai
- Griffith, Linda G.
- Bawendi, Moungi G.
- Kirsch, David G.
- Brigman, Brian E.
- Venue
- Science Translational Medicine
- Published
- 2016-01-06
- Volume
- 8
- Issue
- 320
- Pages
- 320ra4-320ra4
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4794335
- OpenAlex
- W2240104466
- Cited by
- 296
- References
- 40
- Citations by year
- 2026: 24 · 2025: 18 · 2024: 20 · 2023: 23 · 2022: 32 · 2021: 43 · 2020: 36 · 2019: 18 · 2018: 33 · 2017: 31 · 2016: 17
- FWCI
- 13.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- American Society of Clinical Oncology Advanced Clinical Research Award
- NIH (#T32GM007171)
- National Cancer Institute Small Business Innovation Research (#1U43CA165024)
- National Center for Advancing Translational Science (#UL1TR001117)
- Duke Comprehensive Cancer Center Support (5P30-CA-014236-38)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Optical Imaging and Spectroscopy Techniques
- Keywords
- tumor imaging, soft tissue sarcoma, breast cancer, local recurrence, intraoperative tumor detection, tumor bed, pharmacokinetics, lysine labeling
- MeSH terms
- Animals, Breast Neoplasms, Diagnostic Imaging, Disease Models, Animal, Female, Fluorescent Dyes, Humans, Injections, Intravenous, Neoplasms, Peptide Hydrolases, Sarcoma, Tissue Distribution, Mice, Metabolome
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