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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”
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“Moreover, given that proteases that are closely related cleave similar substrates such as the matrix metalloproteinases 90 , cathepsins 91 and caspases 92 , our peptide selection process did not exclude substrates with broad selectivity for proteases within a family nor did it involve a negative…”
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“Fluorescent signal is generated and detected at sites of tumor in the surgical bed and in excised specimens using (1) LUM015, a novel PEGylated protease-activated far-red fluorescent imaging agent [14]; * Barbara L.”
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“In the future, we will replace BLI with indocyanine green (ICG) [39], LUM015 [40], and intraoperative fluorescein [41] for intraoperative detection and analysis in clinical research and applications.”
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Dual-modality optical coherence tomography and fluorescence tethered capsule endomicroscopy
Wartak, A., Kelada, A. K., Alarcon, P. A. L., Bablouzian, A. L., Ahsen, O. O., Gregg, A. L., Wei, Y., Bollavaram, K., Sheil, C. J., Farewell, E., et al. (2021) · Biomedical Optics Express · doi:10.1364/boe.422453 · Cited by 13
Design of cathepsin-sensitive linkers for tumor-selective bioconjugate drug delivery
Giri, A., Shin, Y., Ha, J. J., Chae, S., Shrestha, P., Pham, K., Kwon, T. K., Park, J. H., Jeong, J., Lee, N. K., et al. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114197 · Cited by 12
A Preliminary Study of PSMA Fluorescent Probe for Targeted Fluorescence Imaging of Prostate Cancer
Zhou, H., Liu, Y., Zhang, X., Chen, K., Li, Y., Xu, X., & Xu, B. (2022) · Molecules · doi:10.3390/molecules27092736 · Cited by 12
Fluorescence Imaging of Breast Tumors and Gastrointestinal Cancer
Grosenick, D., & Bremer, C. (2020) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-030-42618-7_18 · Cited by 12
Brennecke, B., Wang, Q., Haap, W. J., Grether, U., Hu, H., & Nazaré, M. (2021) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.0c00699 · Cited by 12
Han, Z., Ke, M., Liu, X., Wang, J., Guan, Z., Qiao, L., Wu, Z., Sun, Y., & Sun, X. (2021) · Molecular Imaging and Biology · doi:10.1007/s11307-021-01631-y · Cited by 12
“microenvironment, which was intravenously injected and confirmed as safe with specific tumor distribution in a Phase 1 safety study for the lead indications of breast cancer [100].”
BackgroundPreclinical Evaluation of Cathepsin-Based Fluorescent Imaging System for Cytoreductive Surgery
Chan, C. H. F., Liesenfeld, L. F., Ferreiro-Neira, I., & Cusack, J. C. (2016) · Annals of Surgical Oncology · doi:10.1245/s10434-016-5690-5 · Cited by 12
“They have shown that LUM015 is activated and accumulated in the tumors, making the agent more tumor-specific compared with adjacent normal tissues.(6) In our study, we have shown the utility of the LUM Imaging System in detecting small peritoneal tumors (\2.”
BackgroundMethodInfluentialSamkoe, K. S., Sardar, H. S., Gunn, J. R., Elliott, J. T., Mansur, S., Feldwisch, J., Pogue, B. W., Linos, K. D., Paulsen, K. D., & Henderson, E. R. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0378 · Cited by 11
Esfahani, S. A., Heidari, P., Kucherlapati, M. H., Ferrer, J. M., Kucherlapati, R., & Mahmood, U. (2019) · PubMed Central · Cited by 11
Low-Field NMR Relaxometry for Intraoperative Tumour Margin Assessment in Breast-Conserving Surgery
Bitonto, V., Ruggiero, M. R., Pittaro, A., Castellano, I., Bussone, R., Broche, L., Lurie, D. J., Aime, S., Baroni, S., & Crich, S. G. (2021) · Cancers · doi:10.3390/cancers13164141 · Cited by 11
Capillaries segmentation of NIR-II images and its application in ischemic stroke
Hao, Y., Ji, A., Xing, R., Zhu, W., Jiang, B., Jian, Y., & Chen, H. (2022) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2022.105742 · Cited by 11
Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer
Kennedy, G. T., Azari, F. S., Nadeem, B., Chang, A. E., Segil, A., Bernstein, E. R., Desphande, C., Kucharczuk, J. C., Delikatny, E. J., & Singhal, S. K. (2022) · Molecular Imaging · doi:10.1155/2022/5447290 · Cited by 11
“More recently, a cathepsin substrate probe containing a far-red fluorophore, LUM015, was used to image human breast and sarcoma resection specimens [30].”
BackgroundDuru, N., Pawar, N. R., Martin, E. W., Buzza, M. S., Conway, G. D., Lapidus, R. G., Liu, S., Reader, J. C., Rao, G. G., Roque, D. M., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2201423119 · Cited by 10
Evaluation of fluorescence‐guided surgery agents in a murine model of soft tissue fibrosarcoma
Prince, A. C., McGee, A., Siegel, H. J., Rosenthal, E. L., Behnke, N. K., & Warram, J. M. (2017) · Journal of Surgical Oncology · doi:10.1002/jso.24950 · Cited by 10
“EGFR, VEGFR2, αvβ3, and cathepsin B are all shown to be over expressed in STS.8–10,13,14 (Figure 3) reveals all targets were similarly expressed in HT1080.”
BackgroundInfluentialImmunohistochemical Evaluation of Cathepsin B, L, and S Expression in Breast Cancer Patients
Linders, D. G. J., Bijlstra, O. D., Fallert, L. C., Dekker-Ensink, N. G., March, T. L., Pool, M., Walker, E., Straight, B., Basilion, J. P., Bogyo, M. S., et al. (2024) · Molecular Imaging and Biology · doi:10.1007/s11307-024-01955-5 · Cited by 9
Declerck, N. B., Declercq, S., Debie, P., Ville, J. D., Mateusiak, Ł., Saliën, J., Stroet, M. C. M., Luciano, M., Li, D., Schnermann, M. J., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02376 · Cited by 9
Li, M., Zhang, J., He, Q., Yan, W., & Zhang, L. (2023) · Microchemical Journal · doi:10.1016/j.microc.2023.109709 · Cited by 9
Wang, Q., Chen, B., Duan, C., Wang, T., Lou, X., Dai, J. Y., & Xia, F. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.3c05735 · Cited by 9
A matrix metalloproteinase activation probe for painting human tumours
Mills, B., Norberg, D., Dhaliwal, K., Akram, A. R., Bradley, M., & Megía-Fernández, A. (2020) · Chemical Communications · doi:10.1039/d0cc03886e · Cited by 9
Osborn, E. A., Ughi, G. J., Verjans, J. W. H., Piao, Z., Gerbaud, É., Albaghdadi, M. S., Khraishah, H., Kassab, M. B., Takx, R. A. P., Cui, J., et al. (2021) · JACC. Cardiovascular imaging · doi:10.1016/j.jcmg.2021.06.017 · Cited by 9
Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism
Gutierrez, W. R., Scherer, A., Rytlewski, J. D., Laverty, E. A., Sheehan, A. P., McGivney, G. R., Brockman, Q. R., Knepper-Adrian, V., Roughton, G. A., Quelle, D. E., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.159419 · Cited by 9
Cancer diagnostics: On-target probes for early detection
Hori, S. S., Tummers, W. S. F. J., & Gambhir, S. S. (2017) · Nature Biomedical Engineering · doi:10.1038/s41551-017-0062 · Cited by 9
Advances in Intraoperative Glioma Tissue Sampling and Infiltration Assessment
Al-Adli, N. N., Young, J. S., Scotford, K., Sibih, Y., Payne, J., & Berger, M. S. (2023) · Brain Sciences · doi:10.3390/brainsci13121637 · Cited by 8
“Novel fluorophores, such as LUM015 [35] Pantimumab-IRDye800CW [36,37], BLZ-100 [36,38–40], Cetuximab-IRDye800CW [41–43], 68 Ga-BBN-IRDye800CW [44], ABY-029 [45], and Demeclocycline [46,47], attempt to overcome the limitations associated with the passive accumulation of existing agents by targeting…”
BackgroundIntraoperative Margin Trials in Breast Cancer
Armani, A., Borst, J. M., Douglas, S. R., Goldharber, N., Taj, R., & Blair, S. L. (2022) · Current Breast Cancer Reports · doi:10.1007/s12609-022-00450-6 · Cited by 8
Multimodal Contrast Agents for Optoacoustic Brain Imaging in Small Animals
Shi, X., Ji, B., Kong, Y., Guan, Y., & Ni, R. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.746815 · Cited by 8
“A few fluorescence imaging contrast agents are in clinical trials at different 0stages including ONM-100 (pH-activable NP), second window ICG or SWIG, BLZ-100, Tumor PaintTM, TumorGlowTM, ABY-029, LUM015, SMG-101, OTL38, and Cornell dots (Phillips et al., 2014; Whitley et al., 2016; Gutowski et al., 2017; Randall et a…”
BackgroundPreclinical and Coclinical Studies in Prostate CancerPreprint
Chen, M., & Pandolfi, P. P. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a030544 · Cited by 9
Current and Future Applications of Fluorescence-Guided Surgery in Head and Neck Cancer
Martin, E., Hom, M. E., Mani, L., & Rosenthal, E. L. (2022) · Surgical Oncology Clinics of North America · doi:10.1016/j.soc.2022.07.001 · Cited by 7
Agents for Fluorescence-Guided Glioblastoma Surgery
Romeo, E., Tzakos, A. G., Crook, T., Syed, N., Voulgaris, S., & Alexiou, G. Α. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17050637 · Cited by 7
“LUM015 is a PEGylated protease-activated far-red fluorescent imaging probe, which can offer real-time imaging of cancer cells of various tumor types, including GBM [67].”
Epshtein, Y., Blau, R., Pisarevsky, E., Koshrovski‐Michael, S., Ben‐Shushan, D., Pozzi, S., Shenbach‐Koltin, G., Fridrich, L., Buzhor, M. G., Krivitsky, A., et al. (2022) · Theranostics · doi:10.7150/thno.72941 · Cited by 7
“Image-guided surgery (IGS) was developed to assist the surgeon by marking tumor margins in real-time with imaging agents that can be visualized by advanced imaging devices.”
BackgroundInfluentialHwang, J., Cheney, P. P., Kanick, S. C., Le, H. N. D., McClatchy, D. M., Zhang, H., Liu, N., Lu, Z.-Q. J., Cho, T. J., Briggman, K. A., et al. (2024) · Journal of Biomedical Optics · doi:10.1117/1.jbo.29.9.093503 · Cited by 7
Quantitative pharmacokinetic and biodistribution studies for fluorescent imaging agents
Feng, Y., Pannem, S., Hodge, S., Rounds, C. C., Tichauer, K. M., Paulsen, K. D., & Samkoe, K. S. (2024) · Biomedical Optics Express · doi:10.1364/boe.504878 · Cited by 7
“Similarly, the PK and BD analysis of LUM015 was performed with a combination of LC-MS/MS and HPLC with fluorescence detection, respectively, using the supernatant from chemically extracted and precipitated plasma and tissue homogenates [21].”
Chitalia, R., Mueller, J. L., Fu, H. L., Whitley, M. J., Kirsch, D. G., Brown, J. Q., Willett, R. M., & Ramanujam, N. (2016) · Biomedical Optics Express · doi:10.1364/boe.7.003412 · Cited by 7
Current Opportunities and Future Vision of Precision Medicine in Radiation Oncology
Kirsch, D. G. (2018) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2017.04.005 · Cited by 7
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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