{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Whitley MJ"],"funding":["NCATS NIH HHS","American Society of Clinical Oncology Advanced Clinical Research Award","Duke Comprehensive Cancer Center Support","National Cancer Institute Small Business Innovation Research","National Center for Advancing Translational Science","NCI NIH HHS","NIH","NIGMS NIH HHS"],"pagination":["320ra4"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4794335"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(320)"],"pubmed_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."],"journal":["Science translational medicine"],"pubmed_title":["A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer."],"pmcid":["PMC4794335"],"funding_grant_id":["P01 CA080124","UL1TR001117","R35 CA197743","#T32GM007171","UL1 TR001117","R01 CA126642","P30 CA014236","T32GM007171","5P30-CA-014236-38","1U43CA165024","R01 CA096915","P30 CA014051","P50 CA127003","#1U43CA165024","#UL1TR001117","U43 CA165024","T32 GM007171"],"pubmed_authors":["Mosca PJ","Blazer DG","Lazarides AL","O'Reilly EK","Spasojevic I","Ferrer JM","Mito JK","Greenup RA","Fukumura D","Jain RK","Bawendi MG","Snuderl M","Riedel RF","Strasfeld DB","Larrier NA","Cuneo KC","Lee WD","Lee CL","Kirsch DG","Cahill J","Cardona DM","Brigman BE","Eward WC","Griffith LG","Whitley MJ","Hwang ES"],"additional_accession":[]},"is_claimable":false,"name":"A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.","description":"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.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Jan","modification":"2024-11-20T00:19:49.578Z","creation":"2019-03-27T02:11:15Z"},"accession":"S-EPMC4794335","cross_references":{"pubmed":["26738797"],"doi":["10.1126/scitranslmed.aad0293"]}}