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Mito, Jeffrey

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Mito

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Mito, Jeffrey

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2016 - 20182

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Author's Publications: search.filters.isAuthorOfPublication.3f7673d9-3b7b-43e7-85f3-3708f96dec25

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    A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer
    (American Association for the Advancement of Science (AAAS), 2016) Whitley, Melodi; Cardona, Diana M.; Lazarides, Alexander; Spasojevic, Ivan; Ferrer, Jorge; Cahill, Joan; Lee, Chang-Lung; Snuderl, Matija; Blazer, Dan; Hwang, E. Shelley; Greenup, Rachel; Mosca, Paul; Mito, Jeffrey; Cuneo, Kyle C.; Larrier, Niole A.; OReilly, Erin K.; Riedel, Richard F.; Eward, William C.; Strasfeld, David B.; Fukumura, Dai; Jain, Rakesh; Lee, W. David; Griffith, Linda G.; Bawendi, Moungi G.; Kirsch, David G.; Brigman, Brian E.
    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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    Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma
    (American Association for the Advancement of Science (AAAS), 2018-11-01) Ablain, Julien; Xu, Mengshu; Rothschild, Harriet; Jordan, Richard C.; Mito, Jeffrey; Daniels, Brianne H.; Bell, Caitlin F.; Joseph, Nancy M.; Wu, Hong; Bastian, Boris C.; Zon, Leonard; Yeh, Iwei
    Melanomas originating from mucosal surfaces have low mutation burden, genomic instability, and poor prognosis. To identify potential driver genes, we sequenced hundreds of cancer-related genes in 43 human mucosal melanomas, cataloguing point mutations, 5 amplifications and deletions. The SPRED1 gene, which encodes a negative regulator of MAPK signaling, was inactivated in 37% of the tumors. Four distinct genotypes were associated with SPRED1 loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, we found that SPRED1 functions as a tumor suppressor, particularly in the context of KIT mutations. SPRED1 knockdown caused MAPK 10 activation, increased cell proliferation and conferred resistance to drugs inhibiting KIT tyrosine kinase activity. These findings provide a rationale for MAPK inhibition in SPRED1-deficient melanomas and introduce a zebrafish modeling approach that can be used more generally to dissect genetic interactions in cancer.