Cited by 296Protease and Inhibitor MechanismsNanoplatforms for cancer theranosticsOptical Imaging and Spectroscopy Techniques

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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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Whitley, Melodi Javid, Cardona, Diana M., Lazarides, Alexander L., Spasojevic, Ivan, Ferrer, Jorge M., Cahill, Joan, Lee, Chang-Lung, Snuderl, Matija, Blazer, Dan G., Hwang, E. Shelley, Greenup, Rachel A., Mosca, Paul J., Mito, Jeffrey K., Cuneo, Kyle C., Larrier, Nicole A., O’Reilly, Erin K., Riedel, Richard F., Eward, William C., Strasfeld, David B., Fukumura, Dai, Jain, Rakesh K., Lee, W. David, Griffith, Linda G., Bawendi, Moungi G., Kirsch, David G., Brigman, Brian E.·2016·Science Translational Medicine

DOI 10.1126/scitranslmed.aad0293PMC PMC4794335

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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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Additional file 1 of Intraoperative fluorescence imaging with aminolevulinic acid detects grossly occult breast cancer: a phase II randomized controlled trial
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Additional file 1 of Acoustofluidic assembly of primary tumor-derived organotypic cell clusters for rapid evaluation of cancer immunotherapy
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Additional file 6 of Intraoperative fluorescence imaging with aminolevulinic acid detects grossly occult breast cancer: a phase II randomized controlled trial
Ottolino‐Perry, K., Shahid, A., DeLuca, S., Son, V., Sukhram, M., Meng, F., Liu, Z. (. A., Rapic, S., Anantha, N. T., Wang, S. C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14966342
Additional file 4 of Intraoperative fluorescence imaging with aminolevulinic acid detects grossly occult breast cancer: a phase II randomized controlled trial
Ottolino‐Perry, K., Shahid, A., DeLuca, S., Son, V., Sukhram, M., Meng, F., Liu, Z. (. A., Rapic, S., Anantha, N. T., Wang, S. C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14966333
Additional file 1 of Novel multifunctional NIR-II aggregation-induced emission nanoparticles-assisted intraoperative identification and elimination of residual tumor
Qu, Q., Zhang, Z., Guo, X., Yang, J., Cao, C., Li, C., Zhang, H., Xu, P., Hu, Z., & Tian, J. (2022) · Figshare · doi:10.6084/m9.figshare.19387767
Additional file 5 of Intraoperative fluorescence imaging with aminolevulinic acid detects grossly occult breast cancer: a phase II randomized controlled trial
Ottolino‐Perry, K., Shahid, A., DeLuca, S., Son, V., Sukhram, M., Meng, F., Liu, Z. (. A., Rapic, S., Anantha, N. T., Wang, S. C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14966339
Additional file 2 of Intraoperative fluorescence imaging with aminolevulinic acid detects grossly occult breast cancer: a phase II randomized controlled trial
Ottolino‐Perry, K., Shahid, A., DeLuca, S., Son, V., Sukhram, M., Meng, F., Liu, Z. (. A., Rapic, S., Anantha, N. T., Wang, S. C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14966324
Additional file 7 of Intraoperative fluorescence imaging with aminolevulinic acid detects grossly occult breast cancer: a phase II randomized controlled trial
Ottolino‐Perry, K., Shahid, A., DeLuca, S., Son, V., Sukhram, M., Meng, F., Liu, Z. (. A., Rapic, S., Anantha, N. T., Wang, S. C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14966345
Additional file 1 of Targeted imaging of esophageal adenocarcinoma with a near-infrared fluorescent peptide
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Additional file 1 of Fluorescent image-guided surgery in breast cancer by intravenous application of a quenched fluorescence activity-based probe for cysteine cathepsins in a syngeneic mouse model
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Additional file 3 of Intraoperative fluorescence imaging with aminolevulinic acid detects grossly occult breast cancer: a phase II randomized controlled trial
Ottolino‐Perry, K., Shahid, A., DeLuca, S., Son, V., Sukhram, M., Meng, F., Liu, Z. (. A., Rapic, S., Anantha, N. T., Wang, S. C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14966330
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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
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2016-01-06
Volume: 8
Issue: 320
Pages: 320ra4-320ra4
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.aad0293
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
Licence: www.sciencemag.org/about/science-licenses-journal-article-reuse (vor, 366 d)
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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A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer

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